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Kinetic network model to explain gain-of-function mutations in ERK2 enzyme
Mikita Misiura1, Anatoly B Kolomeisky1
1Department of Chemistry, Rice University, Houston, Texas 77005-1892, USA.
The Journal of Chemical Physics
|April 22, 2019
Summary
A "sevenmaker" mutation in ERK2 protein kinase enhances its activity by altering enzyme-substrate interactions. This study models how weakened interactions can paradoxically boost catalytic efficiency, explaining disease-linked pathway overactivation.
Area of Science:
- Biochemistry and Molecular Biology
- Systems Biology
- Enzyme Kinetics
Background:
- The Ras/Raf/MEK/ERK signaling pathway is crucial for cellular responses but its dysregulation, often due to mutations, drives diseases like cancer.
- The ERK2 (Extracellular signal-regulated kinase 2) protein is a key component of this pathway, and specific mutations can lead to its hyperactivation.
- A known "gain-of-function" mutation in ERK2, the "sevenmaker" mutation (D319N), increases its activity in vivo, but the underlying molecular mechanism remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanism behind the increased activity of the ERK2 "sevenmaker" mutant.
- To develop a theoretical model explaining how a mutation can paradoxically enhance enzyme activity despite disrupting interactions.
- To investigate the relationship between enzyme-substrate interaction energy and catalytic efficiency in ERK2.
Main Methods:
- Development of a semiquantitative kinetic network model for ERK2, treating it as a system of coupled Michaelis-Menten processes.
- Utilized the method of first-passage processes to calculate the dynamic properties of the ERK2 biochemical network.
- Analyzed the impact of altered interaction energy between ERK2 and its substrates on kinetic properties.
Main Results:
- The study presents a model where the "sevenmaker" mutation's effect is linked to changes in enzyme-substrate interaction energy.
- Demonstrated a nonmonotonic dependence of ERK2 kinetic properties on interaction energy, suggesting that weakened interactions can sometimes enhance catalytic efficiency.
- Theoretical predictions from the model align with experimental observations of the "sevenmaker" mutation's effect on ERK2 activity.
Conclusions:
- The increased activity of the ERK2 "sevenmaker" mutant can be explained by changes in enzyme-substrate interaction energy, leading to enhanced catalytic properties.
- This work highlights that mutations weakening intermolecular interactions may paradoxically improve enzyme function.
- The study suggests that substrate concentrations might also influence the effect of mutations on enzyme activity.
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