Lipid molecules induce p38α activation via a novel molecular switch

Yael Eisenberg-Domovich ¹ Netanel Tzarum ¹ Joell J. Gills ² Phillip A. Dennis ² Oded Livnah ¹

¹The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem
²Medical Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland

p38α MAP kinase 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 p38α autoactivation and
apoptosis. Perifosine, an Akt inhibitor in Phase II clinical trials, also showed
p38α activation properties similarly to those of PIAs. The crystal structures of p38α 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 MAP kinase insert region. In addition, there are
conformational changes in the αEF/αF loop region which act as an activation switch,
inducing autophosphorylation. The lipid binding site also accommodates hydrophobic
inhibitor molecules, and thus can serve as a novel p38α-target for specific activation or
inhibition, with novel therapeutic implications.