Dissecting the self-assembly kinetics of multimeric pore-forming toxins
A A Lee1, M J Senior2, M I Wallace2
1Mathematical Institute, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, Oxfordshire, UK School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 01238, USA.
Journal of the Royal Society, Interface
|January 15, 2016
Summary
This study introduces a kinetic model for pore-forming toxins, explaining their cell-killing mechanism. The model accurately predicts pore formation rates and concentrations, offering insights into error-free self-assembly.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Pore-forming toxins (PFTs) are critical virulence factors and immune effectors.
- PFTs assemble into multimeric pores on cell membranes, leading to cell death.
- Quantitative understanding of PFT self-assembly kinetics is limited.
Purpose of the Study:
- To develop an analytically solvable kinetic model for stepwise, reversible PFT oligomerization.
- To provide quantitative expressions for pore formation rate and concentration.
- To explain observed self-assembly dynamics, including low intermediate concentrations.
Main Methods:
- Development of a stepwise, reversible oligomerization kinetic model.
- Derivation of algebraic expressions for pore formation kinetics.
- Comparison of model predictions with experimental data from multiple PFTs.
Main Results:
- The model provides simple algebraic expressions for pore formation rate and concentration.
- Quantitative agreement was achieved with experimental data for Bacillus thuringiensis Cry1Ac, aerolysin, Staphylococcus aureus α-haemolysin, and Escherichia coli cytolysin A.
- The model explains rapid self-assembly with low oligomeric intermediate concentrations.
Conclusions:
- The proposed kinetic model accurately describes PFT self-assembly.
- Suppressing oligomeric intermediates may be crucial for reliable, error-free pore formation.
- This work provides a quantitative framework for understanding PFT pore assembly.
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