Lipid Molecules Induce p38α Activation via a Novel Molecular Switch

p38 alpha mitogen-activated protein kinase (MAPK) is generally activated by dual phosphorylation but has also been shown to exhibit alternative activation modes. One of these modes included a direct interaction with phosphatidylinositol ether lipid analogues (PIA) inducing p38 alpha autoactivation and apoptosis. Perifosine, an Akt inhibitor in phase II clinical trials, also showed p38 alpha activation properties similarly to those of PI As. The crystal structures of p38 alpha in complex with PIA23, PIA24 and perifosine provide insights into this unique activation mode. The activating molecules bind a unique hydrophobic binding site in the kinase C'-lobe formed in part by the MAPK insert region. In addition, there are conformational changes in the short alpha EF/alpha F loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the alpha EF/alpha F loop identified Trp197 as a key residue in the lipid binding and in p38 alpha catalytic activity. The lipid binding site also accommodates hydrophobic inhibitor molecules and, thus, can serve as a novel p38 alpha-target for specific activation or inhibition, with novel therapeutic implications. (C) 2012 Elsevier Ltd. All rights reserved.