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Mutation in the Common Docking Domain Affects MAP Kinase ERK2 Catalysis and Stability
Leonore Novak1, Maria Petrosino2, Alessandra Pasquo3
1Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
Cancers
|June 10, 2023
Summary
Mutations in the ERK2 docking site impact its function and stability. This study analyzes how these changes affect cancer-related signaling pathways, revealing potential therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Cellular Signaling
Background:
- Extracellular-signal-regulated kinase 2 (ERK2) is a key mitogen-activated protein kinase (MAPK) in the Ras-Raf-MEK-ERK pathway.
- ERK2 signaling is crucial for cellular processes and its deregulation is linked to human diseases, notably cancer.
- The common docking site (CD-site) of ERK2 is vital for substrate and regulator interactions.
Purpose of the Study:
- To conduct a comprehensive biophysical analysis of wild-type and variant human ERK2 (non-phosphorylated and phosphorylated).
- To investigate the impact of missense mutations in the ERK2 CD-site on its structure, function, and stability.
- To understand how point mutations affect the ERK2 structure-function relationship in the context of cancer.
Main Methods:
- Purification of recombinant human non-phosphorylated (NP-) and phosphorylated (P-) ERK2 wild-type and missense variants.
- Comprehensive biophysical analysis including structural, functional, and stability assays.
- Characterization of variants located in the common docking site (CD-site).
Main Results:
- Most P-ERK2 variants in the CD-site exhibited reduced catalytic efficiency.
- Specific variants (P-ERK2 D321E, D321N, D321V, E322K) showed altered thermodynamic stability.
- Thermal stability was decreased in NP-ERK2 and P-ERK2 variants (D321E, D321G, E322K) compared to wild-type.
Conclusions:
- Single residue mutations in the ERK2 CD-site can induce local structural changes.
- These structural alterations lead to changes in global ERK2 stability and catalytic activity.
- Understanding these mutations' effects is crucial for deciphering ERK2's role in disease and developing targeted therapies.
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