PDK-1 Signaling Pathway
As a member of AGC kinases family, PDK-1, a protein of 556 amino acids, is
composed of serine and threonine kinases. The catalytic domain of these serine and
threonine kinases show a sequential similarity with cAMP-dependent protein kinase
1 (PKA), cGMP-dependent protein kinase (PKG) and protein kinase C (PKC). There are
two phosphorylation sites that many AGC kinases and they are to regulate the
activity of AGC kinases. The one which is located within the kinase domain is called
activation loop, while the other one named hydrophobic motif is located in a region
which is adjacent to the catalytic domain. The enzymatic full activation is triggered by
phosphorylation of activation loop and hydrophobic motif which is catalyzed by an
autophosphorylation reaction. n addition, PDK-1 kinase also has a PH domain.
The PH domain is used for mainly interacting with phosphatidylinositol
(3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate that is essential in
localization and activation of some of membrane associated PDK-1's substrates such
as AKT. The kinase domain has three ligand binding sites, namely the substrate
binding site, the ATP binding site, and the docking site which is also known as PIF
pocket. The PIF pocket interacts and binds some PDK-1 substrates such as S6K and
Protein kinase C . Several small molecule allosteric activators of PDK-1 in previous
studies were shown to inhibit the activation of substrates selectively. Instead of
binding to the active site, these small molecules enable PDK-1 to activate other
substrates which do not require docking site interaction. So far, there is no
well-defined inhibitor for PDK-1. One of the most important substrate of PDK-1 is AKT.
The activation of AKT requires a proper orientation of the kinase and PH domains of
PDK-1 and AKT at the membrane. Many proteins that interact with PDK-1 via a
hydrophobic motif named PDK-1 interacting fragment (PIF).
https://www.creative-diagnostics.com/pdk-1-signaling-pathway.htm
