Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms2687
Keywords
-
Categories
Funding
- NIH [R01AA017238, 1R01CA160457]
- DOD-BCRP [BC100466]
- Eric Dudl Memorial Scholarship
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available