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Structure of the complex between ERK2 phosphomimetic mutant and PEA-15Structure of the complex between ERK2 phosphomimetic mutant and PEA-15
Structural highlights
Publication Abstract from PubMedERK1/2 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. 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. 2013 Apr 9;4:1681. doi: 10.1038/ncomms2687. PMID:23575685[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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