Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation.
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 alphaC 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.
Hauge
Camilla
C
Biotech Research and Innovation Centre, Ole Maaløes vej, Copenhagen N, Denmark.
Antal
Torben L
TL
Hirschberg
Daniel
D
Doehn
Ulrik
U
Thorup
Katrine
K
Idrissova
Leila
L
Hansen
Klaus
K
Jensen
Ole N
ON
Jørgensen
Thomas J
TJ
Biondi
Ricardo M
RM
Frödin
Morten
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000502:physiology; D017433:Protein Structure, Secondary; D015398:Signal Transduction
D036341:Intercellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases