Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1

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, explaining the mechanism of many disease-causing mutations, and ERK2 release is not required for nucleotide exchange, suggesting a processive mechanism. Our data advance the understanding of MAPK signalling and provide a starting point for drug development.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-01-19
DOI
https://doi.org/10.64898/2026.01.19.700303
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1

Jill von Velsen, Oscar Vadas, Nicola Piasentin, Francesco Luigi Gervasio et al.
bioRxiv (Cold Spring Harbor Laboratory)
Melanoma and MAPK Pathways
article

Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1

Jill von Velsen, Oscar Vadas, Nicola Piasentin, Francesco Luigi Gervasio, Karine Lapouge, Pauline Juyoux, Hayden Fisher, Matthew W. Bowler
article en

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, explaining the mechanism of many disease-causing mutations, and ERK2 release is not required for nucleotide exchange, suggesting a processive mechanism. Our data advance the understanding of MAPK signalling and provide a starting point for drug development.

bioRxiv (Cold Spring Harbor Laboratory)
University of Geneva (CH), SIB Swiss Institute of Bioinformatics (CH), Centre National de la Recherche Scientifique (FR), HES-SO University of Applied Sciences and Arts Western Switzerland (CH), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), European Synchrotron Radiation Facility (FR), Protein Express (United States) (US), European Molecular Biology Laboratory (FR), University College London (GB), Université Grenoble Alpes (FR)
National Science Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Centro Svizzero di Calcolo Scientifico, National Supercomputing Centre Singapore
Good health and well-being
Openalex Percentile: Top 84%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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