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Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK

Peter D Mace1, Yann Wallez, Michael F Egger

  • 1Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.

Nature Communications
|April 12, 2013
PubMed

Insights

The scaffolding protein PEA-15 binds ERK1/2 kinases, influencing their activity and localization. This interaction reveals how PEA-15 regulates ERK signaling, impacting cell growth and migration.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • ERK1/2 kinases are crucial for cell proliferation and migration.
  • Dysregulated ERK signaling contributes to oncogenic transformation.
  • PEA-15 scaffolding protein interacts with ERK1/2, affecting its localization and phosphorylation.

Purpose of the Study:

  • To elucidate the structural basis of PEA-15 interaction with ERK2.
  • To understand how PEA-15 affects ERK2 phosphorylation states and activity.

Main Methods:

  • X-ray crystallography to determine structures of PEA-15 bound to ERK2 phospho-conformers.
  • Analysis of protein-protein interactions and allosteric effects.

Main Results:

  • PEA-15 binds ERK2 via a bipartite mode, occupying two docking sites.
  • PEA-15 interacts with the ERK2 activation loop across different phosphorylation states.
  • PEA-15 binding induces allosteric changes in dually phosphorylated ERK2, inhibiting its active features while protecting it from dephosphorylation.

Conclusions:

  • PEA-15 acts as a dynamic regulator of ERK2 activity.
  • The structural insights explain PEA-15's role in controlling ERK signaling pathways.
  • PEA-15 inhibition primes ERK2 for rapid activation upon release.

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