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

Author

Listed:
  • Peter D. Mace

    (Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute)

  • Yann Wallez

    (Program in Signal Transduction, Cancer Center, Sanford-Burnham Medical Research Institute)

  • Michael F. Egger

    (Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute)

  • Małgorzata K Dobaczewska

    (Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute)

  • Howard Robinson

    (Brookhaven National Laboratory)

  • Elena B. Pasquale

    (Program in Signal Transduction, Cancer Center, Sanford-Burnham Medical Research Institute
    University of California San Diego)

  • Stefan J. Riedl

    (Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute)

Abstract

ERK1/2 kinases are the principal effectors of a central signalling cascade that converts extracellular stimuli into cell proliferation and migration responses and, when deregulated, can promote cell oncogenic transformation. The scaffolding protein PEA-15 is a death effector domain protein that directly interacts with ERK1/2 and affects ERK1/2 subcellular localization and phosphorylation. Here, to understand this ERK1/2 signalling complex, we have solved the crystal structures of PEA-15 bound to three different ERK2 phospho-conformers. The structures reveal that PEA-15 uses a bipartite binding mode, occupying two key docking sites of ERK2. Remarkably, PEA-15 can efficiently bind the ERK2 activation loop in the critical Thr-X-Tyr region in different phosphorylation states. PEA-15 binding triggers an extended allosteric conduit in dually phosphorylated ERK2, disrupting key features of active ERK2. At the same time PEA-15 binding protects ERK2 from dephosphorylation, thus setting the stage for immediate ERK activity upon its release from the PEA-15 inhibitory complex.

Suggested Citation

  • Peter D. Mace & Yann Wallez & Michael F. Egger & Małgorzata K Dobaczewska & Howard Robinson & Elena B. Pasquale & Stefan J. Riedl, 2013. "Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2687
    DOI: 10.1038/ncomms2687
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