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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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Cites
PROCHECK: a program to check the stereochemical quality of protein structures
Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889892009944 · Cited by 24,581
SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling
Guex, N., & Peitsch, M. C. (1997) · Electrophoresis · doi:10.1002/elps.1150181505 · Cited by 11,297
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,014
Alessi, D. R., James, S. R., Downes, C. P., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., & Cohen, P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00122-9 · Cited by 2,874
Goodford, P. J. (1985) · Journal of Medicinal Chemistry · doi:10.1021/jm00145a002 · Cited by 2,642
Franke, T. F., Yang, S., Chan, T. O., Datta, K., Kazlauskas, A., Morrison, D. K., Kaplan, D. R., & Tsichlis, P. N. (1995) · Cell · doi:10.1016/0092-8674(95)90534-0 · Cited by 2,001
Knighton, D. R., Zheng, J., Eyck, L. F. T., Ashford, V. A., Xuong, N., Taylor, S. S., & Sowadski, J. M. (1991) · Science · doi:10.1126/science.1862342 · Cited by 1,764
The Conformational Plasticity of Protein Kinases
Huse, M., & Kuriyan, J. (2002) · Cell · doi:10.1016/s0092-8674(02)00741-9 · Cited by 1,760
Dual Role of Phosphatidylinositol-3,4,5-trisphosphate in the Activation of Protein Kinase B
Stokoe, D., Stephens, L. R., Copeland, T., Gaffney, P. R. J., Reese, C. B., Painter, G. F., Holmes, A. B., McCormick, F. P., & Hawkins, P. T. (1997) · Science · doi:10.1126/science.277.5325.567 · Cited by 1,216
Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II
Sturgill, T. W., Ray, L. B., ERIKSON, E., & Maller, J. L. (1988) · Nature · doi:10.1038/334715a0 · Cited by 1,017
Deák, M., Clifton, A. D., Lucocq, J. M., & Alessi, D. R. (1998) · The EMBO Journal · doi:10.1093/emboj/17.15.4426 · Cited by 1,004
Phosphorylation and Activation of p70 s6k by PDK1
Pullen, N., Dennis, P. B., Andjelkovic, M., Dufner, A., Kozma, S. C., Hemmings, B. A., & Thomas, G. (1998) · Science · doi:10.1126/science.279.5351.707 · Cited by 826
Structural Basis for Control by Phosphorylation
Johnson, L. N., & Lewis, R. J. (2001) · Chemical Reviews · doi:10.1021/cr000225s · Cited by 643
Kobayashi, T., & Cohen, P. (1999) · Biochemical Journal · doi:10.1042/bj3390319 · Cited by 602
Multiple pathways control protein kinase C phosphorylation
Parekh, D. B., Ziegler, W. H., & Parker, P. J. (2000) · The EMBO Journal · doi:10.1093/emboj/19.4.496 · Cited by 601
Park, J., Leong, M., Buse, P., Maiyar, A. C., Firestone, G. L., & Hemmings, B. (1999) · EMBO Journal · doi:10.1093/emboj/18.11.3024 · Cited by 588
Alessi, D. R., Kozlowski, M. T., Weng, Q.-P., MORRICE, N. A., & Avruch, J. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70037-5 · Cited by 574
Williams, M. R., Arthur, J. S. C., Balendran, A., KAAY, J. V. D., Poli, V., Cohen, P., & Alessi, D. R. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00441-3 · Cited by 479
Molecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation
Yang, J., Cron, P. D., Thompson, V., Good, V. M., Heß, D., Hemmings, B. A., & Barford, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00550-6 · Cited by 418
Dynamics of cAMP-Dependent Protein Kinase
Johnson, D. A., Akamine, P., Radzio-Andzelm, E., Madhusudan, & Taylor, S. S. (2001) · Chemical Reviews · doi:10.1021/cr000226k · Cited by 393
The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB
Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., & Alessi, D. R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4380 · Cited by 377
Self-citationA phosphoserine‐regulated docking site in the protein kinase RSK2 that recruits and activates PDK1
Frödin, M., Jensen, C. J., Mérienne, K., & Gammeltoft, S. (2000) · The EMBO Journal · doi:10.1093/emboj/19.12.2924 · Cited by 317
Self-citationBiondi, R. M., Cheung, P., Casamayor, A., Deák, M., Currie, R. A., & Alessi, D. R. (2000) · The EMBO Journal · doi:10.1093/emboj/19.5.979 · Cited by 301
Self-citationEngh, R., Girod, A., Kinzel, V., Huber, R., & Bossemeyer, D. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.42.26157 · Cited by 277
Jensen, C. J., Buch, M.-B., Krag, T. O. B., Hemmings, B. A., Gammeltoft, S., & Frödin, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.38.27168 · Cited by 263
Self-citationActivation of p70/p85 S6 kinase by a pathway independent of p21fi ras
Ming, X., Burgering, B. M. T., Wennström, S., Claesson, L., Heldin, C. H., Bos, J. L., Kozma, S. C., & Thomas, G. (1994) · Nature · doi:10.1038/371426a0 · Cited by 206
Biondi, R. M., Komander, D., Thomas, C. C., Lizcano, J. M., Deak, M., Alessi, D. R., & van Aalten, D. M. F. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf437 · Cited by 203
Self-citationBalendran, A., Biondi, R. M., Cheung, P., Casamayor, A., Deák, M., & Alessi, D. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000421200 · Cited by 183
Self-citationRichards, S. A., Fu, J., Romanelli, A., Shimamura, A., & Blenis, J. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80364-9 · Cited by 142
Dennis, P. B., Pullen, N., Pearson, R. B., Kozma, S. C., & Thomas, G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.24.14845 · Cited by 142
Flynn, P., Mellor, H., Casamassima, A., & Parker, P. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.11064 · Cited by 126
Identification of Serine 380 as the Major Site of Autophosphorylation of Xenopus pp90rsk
Vik, T. A., & Ryder, J. W. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6794 · Cited by 70
The Catalytic Subunit of Dictyostelium cAMP‐Dependent Protein Kinase
Etchebehere, L. C., Bemmelen, M. X. V., Anjard, C., Traincard, F., Assemat, K., Reymond, C., & Véron, M. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.t01-2-00820.x · Cited by 39
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Roux, P. P., & Blenis, J. (2004) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.68.2.320-344.2004 · Cited by 2,540
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., & Su, B. (2006) · Cell · doi:10.1016/j.cell.2006.08.033 · Cited by 1,407
Holz, M. K., Ballif, B. A., Gygi, S. P., & Blenis, J. (2005) · Cell · doi:10.1016/j.cell.2005.10.024 · Cited by 1,262
PI3K/Akt and apoptosis: size matters
Franke, T. F., Hornik, C., Segev, L., Shostak, G. A., & Sugimoto, C. (2003) · Oncogene · doi:10.1038/sj.onc.1207115 · Cited by 1,193
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Magnuson, B., Ekim, B., & Fingar, D. C. (2012) · Biochemical Journal · doi:10.1042/bj20110892 · Cited by 1,015
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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