cd05123

Catalytic domain of AGC family Serine/Threonine Kinases

CDD entry
Member databaseCDD
CDD typedomain
Short nameSTKc_AGC
SetPKc_like

Description

STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. AGC kinases regulate many cellular processes including division, growth, survival, metabolism, motility, and differentiation. Many are implicated in the development of various human diseases. Members of this family include cAMP-dependent Protein Kinase (PKA), cGMP-dependent Protein Kinase (PKG), Protein Kinase C (PKC), Protein Kinase B (PKB), G protein-coupled Receptor Kinase (GRK), Serum- and Glucocorticoid-induced Kinase (SGK), and 70 kDa ribosomal Protein S6 Kinase (p70S6K or S6K), among others. AGC kinases share an activation mechanism based on the phosphorylation of up to three sites: the activation loop (A-loop), the hydrophobic motif (HM) and the turn motif. Phosphorylation at the A-loop is required of most AGC kinases, which results in a disorder-to-order transition of the A-loop. The ordered conformation results in the access of substrates and ATP to the active site. A subset of AGC kinases with C-terminal extensions containing the HM also requires phosphorylation at this site. Phosphorylation at the HM allows the C-terminal extension to form an ordered structure that packs into the hydrophobic pocket of the catalytic domain, which then reconfigures the kinase into an active bi-lobed state. In addition, growth factor-activated AGC kinases such as PKB, p70S6K, RSK, MSK, PKC, and SGK, require phosphorylation at the turn motif (also called tail or zipper site), located N-terminal to the HM at the C-terminal extension. The AGC family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and Phosphoinositide 3-Kinase.
[8, 9, 13, 6, 15, 2, 10, 5, 14, 12, 1, 11, 7, 3, 4]

References

1.Elucidation of characteristic structural features of ligand binding sites of protein kinases: a neural network approach. Niwa T. J Chem Inf Model 46, 2158-66, (2006). PMID: 16995746

2.PDK1, the master regulator of AGC kinase signal transduction. Mora A, Komander D, van Aalten DM, Alessi DR. Semin. Cell Dev. Biol. 15, 161-70, (2004). View articlePMID: 15209375

3.NDR family of AGC kinases--essential regulators of the cell cycle and morphogenesis. Tamaskovic R, Bichsel SJ, Hemmings BA. FEBS Lett 546, 73-80, (2003). PMID: 12829239

4.AGC protein kinase phosphorylation and protein kinase C. Parker PJ, Parkinson SJ. Biochem. Soc. Trans. 29, 860-3, (2001). View articlePMID: 11709088

5.Growth signalling pathways in Arabidopsis and the AGC protein kinases. Bogre L, Okresz L, Henriques R, Anthony RG. Trends Plant Sci 8, 424-31, (2003). PMID: 13678909

6.Systems biology of AGC kinases in fungi. Sobko A. Sci STKE 2006, re9, (2006). PMID: 16971477

7.TOR signaling and S6 kinase 1: Yeast catches up. Powers T. Cell Metab 6, 1-2, (2007). PMID: 17618850

8.The nuts and bolts of AGC protein kinases. Pearce LR, Komander D, Alessi DR. Nat Rev Mol Cell Biol 11, 9-22, (2010). PMID: 20027184

9.Classification and functional annotation of eukaryotic protein kinases. Miranda-Saavedra D, Barton GJ. Proteins 68, 893-914, (2007). PMID: 17557329

10.Structural insights into AGC kinase inhibition. Breitenlechner C, Gassel M, Engh R, Bossemeyer D. Oncol Res 14, 267-78, (2004). PMID: 15206489

11.Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides. Bartlett S, Beddard GS, Jackson RM, Kayser V, Kilner C, Leach A, Nelson A, Oledzki PR, Parker P, Reid GD, Warriner SL. J Am Chem Soc 127, 11699-708, (2005). PMID: 16104747

12.The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Kannan N, Haste N, Taylor SS, Neuwald AF. Proc Natl Acad Sci U S A 104, 1272-7, (2007). PMID: 17227859

13.Lining the pockets of kinases and phosphatases. Gold MG, Barford D, Komander D. Curr Opin Struct Biol 16, 693-701, (2006). PMID: 17084073

14.Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. Hauge C, Antal TL, Hirschberg D, Doehn U, Thorup K, Idrissova L, Hansen K, Jensen ON, Jorgensen TJ, Biondi RM, Frodin M. EMBO J 26, 2251-61, (2007). PMID: 17446865

15.PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle. Dong LQ, Liu F. Am J Physiol Endocrinol Metab 289, E187-96, (2005). PMID: 16014356

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