4IZA

Structure of Dually Phosphorylated ERK2 bound to the PEA-15 Death Effector Domain

Summary for 4IZA

• Entry DOI: 10.2210/pdb4iza/pdb
• Related: 4IZ5 4IZ7
• Descriptor: Mitogen-activated protein kinase 1, Astrocytic phosphoprotein PEA-15 (3 entities in total)
• Functional Keywords: map kinase, death effector domain, transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm, cytoskeleton, spindle (By similarity): P28482; Cytoplasm: Q15121
• Total number of polymer chains: 3
• Total formula weight: 93754.82

Authors

Mace, P.D.,Robinson, H.,Riedl, S.J. (deposition date: 2013-01-29, release date: 2013-04-10, Last modification date: 2024-10-30)

Primary citation

Mace, P.D.,Wallez, Y.,Egger, M.F.,Dobaczewska, M.K.,Robinson, H.,Pasquale, E.B.,Riedl, S.J.
Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.
Nat Commun, 4:1681-1681, 2013

PubMed 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.

PubMed: 23575685
DOI: 10.1038/ncomms2687

Experimental method

X-RAY DIFFRACTION (1.93 Å)