Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel
Journal cover image

Lipid molecules induce p38α activation via a novel molecular switch.

Publication ,  Journal Article
Tzarum, N; Eisenberg-Domovich, Y; Gills, JJ; Dennis, PA; Livnah, O
Published in: J Mol Biol
December 14, 2012

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.

Duke Scholars

Published In

J Mol Biol

DOI

EISSN

1089-8638

Publication Date

December 14, 2012

Volume

424

Issue

5

Start / End Page

339 / 353

Location

Netherlands

Related Subject Headings

  • Sequence Alignment
  • Protein Conformation
  • Protein Binding
  • Phosphatidylinositol Phosphates
  • Molecular Sequence Data
  • Models, Molecular
  • Mitogen-Activated Protein Kinase 14
  • Humans
  • Crystallography, X-Ray
  • Biochemistry & Molecular Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tzarum, N., Eisenberg-Domovich, Y., Gills, J. J., Dennis, P. A., & Livnah, O. (2012). Lipid molecules induce p38α activation via a novel molecular switch. J Mol Biol, 424(5), 339–353. https://doi.org/10.1016/j.jmb.2012.10.007
Tzarum, Netanel, Yael Eisenberg-Domovich, Joell J. Gills, Phillip A. Dennis, and Oded Livnah. “Lipid molecules induce p38α activation via a novel molecular switch.J Mol Biol 424, no. 5 (December 14, 2012): 339–53. https://doi.org/10.1016/j.jmb.2012.10.007.
Tzarum N, Eisenberg-Domovich Y, Gills JJ, Dennis PA, Livnah O. Lipid molecules induce p38α activation via a novel molecular switch. J Mol Biol. 2012 Dec 14;424(5):339–53.
Tzarum, Netanel, et al. “Lipid molecules induce p38α activation via a novel molecular switch.J Mol Biol, vol. 424, no. 5, Dec. 2012, pp. 339–53. Pubmed, doi:10.1016/j.jmb.2012.10.007.
Tzarum N, Eisenberg-Domovich Y, Gills JJ, Dennis PA, Livnah O. Lipid molecules induce p38α activation via a novel molecular switch. J Mol Biol. 2012 Dec 14;424(5):339–353.
Journal cover image

Published In

J Mol Biol

DOI

EISSN

1089-8638

Publication Date

December 14, 2012

Volume

424

Issue

5

Start / End Page

339 / 353

Location

Netherlands

Related Subject Headings

  • Sequence Alignment
  • Protein Conformation
  • Protein Binding
  • Phosphatidylinositol Phosphates
  • Molecular Sequence Data
  • Models, Molecular
  • Mitogen-Activated Protein Kinase 14
  • Humans
  • Crystallography, X-Ray
  • Biochemistry & Molecular Biology