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Mechanism for activation of the growth factor‐activated AGC kinases by turn motif phosphorylation
Author(s) -
Hauge Camilla,
Antal Torben L,
Hirschberg Daniel,
Doehn Ulrik,
Thorup Katrine,
Idrissova Leila,
Hansen Klaus,
Jensen Ole N,
Jørgensen Thomas J,
Biondi Ricardo M,
Frödin Morten
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601682
Subject(s) - kinase , phosphorylation , biology , dephosphorylation , protein kinase domain , allosteric regulation , microbiology and biotechnology , biochemistry , binding site , receptor , gene , phosphatase , mutant
The growth factor/insulin‐stimulated AGC kinases share an activation mechanism based on three phosphorylation sites. Of these, only the role of the activation loop phosphate in the kinase domain and the hydrophobic motif (HM) phosphate in a C‐terminal tail region are well characterized. We investigated the role of the third, so‐called turn motif phosphate, also located in the tail, in the AGC kinases PKB, S6K, RSK, MSK, PRK and PKC. We report cooperative action of the HM phosphate and the turn motif phosphate, because it binds a phosphoSer/Thr‐binding site above the glycine‐rich loop within the kinase domain, promoting zipper‐like association of the tail with the kinase domain, serving to stabilize the HM in its kinase‐activating binding site. We present a molecular model for allosteric activation of AGC kinases by the turn motif phosphate via HM‐mediated stabilization of the αC helix. In S6K and MSK, the turn motif phosphate thereby also protects the HM from dephosphorylation. Our results suggest that the mechanism described is a key feature in activation of upto 26 human AGC kinases.