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

Peter D. Mace, Yann Wallez, Michael F. Egger, Małgorzata K Dobaczewska, Howard Robinson, Elena B. Pasquale and Stefan J. Riedl ()
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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
Stefan J. Riedl: Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2687

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