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

<div class='caption-title'>PEA-15 interacts with ERK2 using a bipartite binding mode</div>
<div class='caption-title'>The PEA-15 death effector domain interacts with the ERK2 DEF-docking site</div>
<div class='caption-title'>PEA-15 binds the ERK2 activation loop in two distinct modes</div>
Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB, Riedl SJ
OpenAccess logo Nat Commun 4 1681 (2013)
Related entries: 4iz5, 4iz7

Cited: 49 times
EuropePMC logo PMID: 23575685

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.

Reviews - 4iza mentioned but not cited (1)

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Articles - 4iza mentioned but not cited (4)

  1. Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB, Riedl SJ. Nat Commun 4 1681 (2013)
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