eLife Assessment: Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1
Year: 2026
Type: peer-review
Abstract: The RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway relays extracellular signals into a cellular response and its dysregulation leads to many pathologies, particularly cancer. Here, we determined cryo-EM structures of the MAP2K MEK1 activating its substrate MAPK ERK2, the final event in the cascade. We define the molecular details of specificity and phosphoryl transfer to the tyrosine of the ERK2 activation loop and examine the mechanism of substrate recognition using solution techniques and molecular dynamics. Binding of the substrate MAPK leads to release of the MAP2K catalytic machinery, a mechanism enhanced in many gain of function disease mutations. Further, we observe that ERK2 release is not required for nucleotide exchange, suggesting how a processive mechanism could proceed. Our data advance the understanding of MAPK signalling and provide a starting point for drug development.Cryo-EM structures of the MEK1-ERK2 complex reveal details of cellular signal transmission.
Author: Julien Roche
Institution: Iowa State University
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Funders: National Science Foundation, European Molecular Biology Laboratory, Equipex, Agence Nationale de la Recherche, European Synchrotron Radiation Facility, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Centre National de la Recherche Scientifique, Université de Genève, Università degli Studi di Torino, French Infrastructure for Integrated Structural Biology, Centro Svizzero di Calcolo Scientifico, National Supercomputing Centre Singapore, National Institutes of Health, University of California, San Francisco, National Institute of Allergy and Infectious Diseases
Awards: G1312572964, CBH-EUR-GS, G256544642, G2568689018, G2659019386, G370692677, G4120410854, G4399195447, G555032910, Cracking the GPCR Code: Decoding Biased Signalling in GPCRs with Machine Learning and Enhanced Sampling for Improved Therapeutics, G678225801, G6803667113, G7240651115, G7259097847, G7293590401, G7351664618, G744475772, National instrumentation in cryo electron microscopy, Infrastructure Française pour la Biologie Structurale Intégrée, G8760597890
OpenAlex ID: W7201859185
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