title: Dissecting the self-assembly kinetics of multimeric pore-forming toxins.
abstract: Pore-forming toxins are ubiquitous cytotoxins that are exploited by both bacteria and the immune response of eukaryotes. These toxins kill cells by assembling large multimeric pores on the cell membrane. However, a quantitative understanding of the mechanism and kinetics of this self-assembly process is lacking. We propose an analytically solvable kinetic model for stepwise, reversible oligomerization. In biologically relevant limits, we obtain simple algebraic expressions for the rate of pore formation, as well as for the concentration of pores as a function of time. Quantitative agreement is obtained between our model and time-resolved kinetic experiments of Bacillus thuringiensis Cry1Ac (tetrameric pore), aerolysin, Staphylococcus aureus α-haemolysin (heptameric pores) and Escherichia coli cytolysin A (dodecameric pore). Furthermore, our model explains how rapid self-assembly can take place with low concentrations of oligomeric intermediates, as observed in recent single-molecule fluorescence experiments of α-haemolysin self-assembly. We propose that suppressing the concentration of oligomeric intermediates may be the key to reliable, error-free, self-assembly of pores.
authors.affiliation: Mathematical Institute, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, Oxfordshire, UK School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 01238, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Lee
authors.affiliation: Physical and Theoretical Chemistry, South Parks Road, Oxford OX1 3QZ.
authors.forename: M J
authors.initials: MJ
authors.lastname: Senior
authors.affiliation: Physical and Theoretical Chemistry, South Parks Road, Oxford OX1 3QZ.
authors.forename: M I
authors.initials: MI
authors.lastname: Wallace
authors.affiliation: Mathematical Institute, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, Oxfordshire, UK.
authors.forename: T E
authors.initials: TE
authors.lastname: Woolley
authors.affiliation: Mathematical Institute, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, Oxfordshire, UK Ian.Griffiths@maths.ox.ac.uk.
authors.forename: I M
authors.initials: IM
authors.lastname: Griffiths
mesh_terms: D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins / Q000737:chemistry*; D001427:Bacterial Toxins / Q000737:chemistry*; D004731:Endotoxins / Q000737:chemistry*; D029968:Escherichia coli Proteins / Q000737:chemistry*; D006460:Hemolysin Proteins / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D054353:Perforin / Q000737:chemistry*; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry*; D020836:Protein Structure, Quaternary
chemical_list: D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004731:Endotoxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D052899:Pore Forming Cytotoxic Proteins; C030956:insecticidal crystal protein, Bacillus Thuringiensis; D054353:Perforin; C032676:aerolysin
keywords: mathematical modelling; pore-forming toxins; reaction kinetics