Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK
Open accessAbstract
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. PEA-15 is a scaffold protein that regulates the localization and phosphorylation of the MAP kinase ERK2. By solving the structure of the PEA-15/ERK2 complex, the authors show that PEA-15 restrains ERK2 in a spring-loaded, activated form.
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ERK is also capable of binding KIM peptides/proteins bi-directionally, as shown for RSK1 and PEA-15.
“a number of recent studies have shown that ERK is also capable of binding KIM peptides/proteins bi-directionally (i.e., RSK1 and PEA-15) 46,53”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [53]
Both aspects of PEA-15 binding on ERK2 were subsequently confirmed by the PEA-15:ERK2 crystal structure.
“Both aspects of PEA-15 binding on ERK2 were subsequently confirmed by the PEA-15:ERK2 crystal structure Fig. 4(C), upper middle].53”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [53]
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- Authors
- Mace, P. D., Wallez, Y., Egger, M. F., Dobaczewska, M. K., Robinson, H., Pasquale, E. B., & Riedl, S. J.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Brookhaven National Laboratory (US)
- Corresponding author
- Riedl, Stefan J.
- Venue
- Nature Communications
- Published
- 2013-04-09
- Volume
- 4
- Issue
- 1
- Pages
- 1681-1681
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3640864
- OpenAlex
- W2083777614
- Cited by
- 97
- References
- 51
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 9 · 2022: 3 · 2021: 5 · 2020: 18 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 5 · 2013: 3
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense (BC100466)
- U.S. Department of Energy
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R01AA017238)
- National Cancer Institute (R01CA160457)
- National Center for Research Resources
- Biological and Environmental Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- ERK2, PEA-15, MAPK signaling, scaffold proteins, protein-protein interaction, allosteric regulation, protein phosphorylation, crystal structure, death effector domain
- MeSH terms
- Amino Acid Sequence, Enzyme Activation, Humans, Models, Molecular, Phosphoproteins, Protein Binding, Protein Conformation, Sequence Homology, Amino Acid, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins
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