Lipid molecules induce p38α activation via a novel molecular switch

Netanel Tzarum, Yael Eisenberg-Domovich, Joell Gills, Phillip A. Dennis, Oded Livnah

Research output: Contribution to journalArticle

Abstract

p38α 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 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 MAPK insert region. In addition, there are conformational changes in the short αEF/αF loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the αEF/αF loop identified Trp197 as a key residue in the lipid binding and in p38α catalytic activity. 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.

Original languageEnglish (US)
Pages (from-to)339-353
Number of pages15
JournalJournal of Molecular Biology
Volume424
Issue number5
DOIs
StatePublished - Dec 14 2012
Externally publishedYes

Fingerprint

Lipids
Binding Sites
Phase II Clinical Trials
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositols
Mitogen-Activated Protein Kinases
Ether
Phosphotransferases
Phosphorylation
Apoptosis
perifosine
Therapeutics

Keywords

  • alternative activation modes
  • MAP kinase
  • p38
  • PIAs
  • protein structure

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Lipid molecules induce p38α activation via a novel molecular switch. / Tzarum, Netanel; Eisenberg-Domovich, Yael; Gills, Joell; Dennis, Phillip A.; Livnah, Oded.

In: Journal of Molecular Biology, Vol. 424, No. 5, 14.12.2012, p. 339-353.

Research output: Contribution to journalArticle

Tzarum, N, Eisenberg-Domovich, Y, Gills, J, Dennis, PA & Livnah, O 2012, 'Lipid molecules induce p38α activation via a novel molecular switch', Journal of Molecular Biology, vol. 424, no. 5, pp. 339-353. https://doi.org/10.1016/j.jmb.2012.10.007
Tzarum, Netanel ; Eisenberg-Domovich, Yael ; Gills, Joell ; Dennis, Phillip A. ; Livnah, Oded. / Lipid molecules induce p38α activation via a novel molecular switch. In: Journal of Molecular Biology. 2012 ; Vol. 424, No. 5. pp. 339-353.
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