title: Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.
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.
authors.affiliation: Program in Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Yann
authors.initials: Y
authors.lastname: Wallez
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egger
authors.forename: Małgorzata K
authors.initials: MK
authors.lastname: Dobaczewska
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Riedl
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008958:Models, Molecular; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases