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A phosphoserine/threonine‐binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation
Author(s) -
Frödin Morten,
Antal Torben L.,
Dümmler Bettina A.,
Jensen Claus J.,
Deak Maria,
Gammeltoft Steen,
Biondi Ricardo M.
Publication year - 2002
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 - 10.1093/emboj/cdf551
Subject(s) - phosphoserine , phosphorylation , biology , kinase , protein serine threonine kinases , biochemistry , threonine , phosphorylation cascade , serine , microbiology and biotechnology , map2k7 , binding site , map kinase kinase kinase , protein phosphorylation , protein kinase a , cyclin dependent kinase 2
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, PKBα, 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 αC‐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.