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Molecular basis of MAPK-activated protein kinase 2:p38 assembly

Andre White1, Christopher A Pargellis, Joey M Studts

  • 1Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. awhite@rdg.hoehringer-ingelheim.com

Proceedings of the National Academy of Sciences of the United States of America
|March 31, 2007
PubMed

Insights

The crystal structure reveals how p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) bind. This interaction is crucial for regulating proinflammatory cytokine production and other cellular responses.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • p38 MAPK and MK2 are critical in cellular signaling, particularly in cytokine production.
  • Their physical association is vital for signal transduction.
  • Understanding this interaction is key to deciphering cellular responses.

Purpose of the Study:

  • To determine the atomic structure of the unphosphorylated p38alpha and MK2 complex.
  • To elucidate the molecular basis of their interaction and regulation.
  • To provide structural insights into signal transduction pathways.

Main Methods:

  • X-ray crystallography at 2.7-A resolution.
  • Analysis of protein-protein interactions within the complex.
  • Identification of key binding regions and motifs.

Main Results:

  • The p38alpha and MK2 kinases form a head-to-head heterodimer.
  • Extensive intermolecular interactions stabilize the complex.
  • Specific MK2 regions (Ile-366-Ala-390 and residues 345-365) bind to p38alpha, influencing activity and localization.

Conclusions:

  • The determined structure reveals novel insights into p38alpha and MK2 regulation.
  • It explains the tight binding and functional importance of the noncatalytic regions.
  • Provides a structural foundation for understanding related signaling pathways and protein interactions.

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