A Novel Lipid Binding Site Formed by the MAP Kinase Insert in p38α

Ron Diskin, David Engelberg, Oded Livnah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The p38 mitogen-activated protein (MAP) kinases function as signaling molecules essential for many cellular processes, particularly mediating stress response. The activity of p38 MAP kinases is meticulously regulated to reach the desired cellular phenotype. Several alternative activation and attenuation mechanisms have been characterized recently which include new phosphorylation sites. Here we present the crystal structure of p38α MAP kinase in complex with n-octyl-β-glucopyranoside detergent. The complex unveils a novel lipid-binding site formed by a local conformational change of the MAP kinase insert. This binding is the first attribution for a possible role of the MAP kinase insert in p38. The binding site can accommodate a large selection of lipidic molecules. In addition, we also show via biophysical methods that arachidonic acid and its derivatives bind p38α in vitro. Based on our analysis we propose that the binding of lipids could fine-tune p38α catalytic activity towards a preferred phenotype.

Original languageAmerican English
Pages (from-to)70-79
Number of pages10
JournalJournal of Molecular Biology
Volume375
Issue number1
DOIs
StatePublished - 4 Jan 2008

Bibliographical note

Funding Information:
This work was supported by Israeli Science Foundation (ISF) grants 495-03 (to O. L.) and funds from the Altertum Elsa and Elyahu Pen Foundations (to O. L. and D. E.). We acknowledge Dr Hagit Zer from the Biacore unit, and Dr Ofra Moshel from the mass spectrometry unit for their contribution to this work. We also thank the ESRF staff for their assistance and ongoing support.

Keywords

  • MAP kinase insert
  • lipid binding site
  • p38
  • protein crystallography
  • structure analysis

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