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Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer

Ernst Ter Haar1, Prakash Prabakhar1, Xun Liu1

  • 1Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139.

The Journal of Biological Chemistry
|January 27, 2007
PubMed

Insights

The p38 signaling pathway, crucial for stress response, involves p38alpha and MAPKAP kinase 2 (MK2). Their heterodimer structure reveals a mechanism preventing premature activation, ensuring proper cell stress response.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Protein kinase structure and function

Background:

  • The p38 signaling pathway is activated by cellular stress, leading to the production of pro-inflammatory cytokines.
  • p38alpha kinase is activated by MKK3/MKK6 and phosphorylates substrates like MAPKAP kinase 2 (MK2).
  • Understanding the regulation of p38alpha-MK2 interaction is key to controlling inflammatory responses.

Purpose of the Study:

  • To determine the crystal structure of the unphosphorylated p38alpha-MK2 heterodimer.
  • To elucidate the structural basis for the regulation of p38alpha and MK2 activity.
  • To identify mechanisms preventing kinase activation in the absence of cellular stress.

Main Methods:

  • X-ray crystallography to determine the 3D structure of the p38alpha-MK2 heterodimer.
  • Biochemical assays to assess kinase activity and phosphorylation states.

Main Results:

  • The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined.
  • The C-terminal regulatory domain of MK2 docks onto p38alpha, with ATP-binding sites at the heterodimer interface.
  • This conformation suggests an inhibitory mechanism preventing substrate phosphorylation without cell stress.
  • Addition of active MKK6-DD rapidly phosphorylated the p38alpha-MK2 heterodimer.

Conclusions:

  • The p38alpha-MK2 heterodimer structure reveals an intrinsic regulatory mechanism.
  • This mechanism prevents inappropriate activation of the p38 pathway under basal conditions.
  • Structural insights can inform the development of targeted therapeutics for inflammatory diseases.

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