Abstract
A new role for protein self-association in the cell is discussed. An argument is advanced that when cellular protein is in its associated state the excluded volume component of the solution is minimized. Conversely, when cellular protein is in its dissociated state the excluded volume component of the solution is maximized. For proteins that make up a substantial fraction of the intracellular protein concentration, control of the self-association event thus presents itself as a means of regulating cellular processes that are influenced by different levels of volume exclusion. In this communication we examine how the control of protein association/dissociation might influence one such important process, namely the folding of a protein to a compact state.
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Notes
The physical justification of this formulation lies in the definition of the equilibrium constant and the separable nature of the chemical potential of species i into ideal and non-ideal components (μ i = μ i IDEAL + μ i NON-IDEAL). For example we note that K B = exp{−(μBIG−μSMALL)/(RT)} = exp{−Δ μIDEAL/(RT)}× exp{−Δ μNON-IDEAL/(RT)}. Thus we may identify K oB with the ideal component exp{−Δ μIDEAL/(RT)} and Ψ with the non-ideal component exp{−Δ μNON-IDEAL/(RT)}. We calculate ψ = exp{−Δ μNON-IDEAL/(RT)}= f BIG/f SMALL by using the Monte-Carlo procedure to define the ratio f BIG/f SMALL. Further information on equilibrium constants and non-ideality can be found (Section 2 of Hall and Minton 2003; Dill and Bromberg 2003).
Reviewer 1 and 2 have posed the following questions worthy of further study. (1) How would the proposed fine tuning effect discussed above be itself affected by different combinations of time scales for protein folding (blue protein) and protein self-association (red protein) events?. (2) How local might the proposed effects be within the cell?. (3) How would increasing the complexity of the starting mixture (eg. various sizes and shapes) and the geometry of the aggregate affect the proposed fine tuning mechanism? Answers to questions 1 and 2 might be provided by more detailed kinetic based simulations of the type conducted (Eleock 2003). An answer to question 3 would require reworking the simulations with size and shape parameters chosen from a more detailed consideration of the relevant composition of macromolecules inside a particular area of the cell.
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Acknowledgements
I would like to acknowledge Prof. C.M. Dobson for providing me with exceptional support during my stay as a postdoctoral fellow at his laboratory. I would also like to thank Prof. Dobson for helpful discussions on this and other topics. Conversations with B. Ruotolo and N. Hirota were much appreciated. Thanks also go to the two anonymous reviewers for a careful review of the manuscript and for providing a number of helpful suggestions. Finally I would like to thank the Human Frontiers International Science Program (HFSP) for financial assistance in the form of a HFSP long term fellowship.
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Hall, D. Protein self-association in the cell: a mechanism for fine tuning the level of macromolecular crowding?. Eur Biophys J 35, 276–280 (2006). https://doi.org/10.1007/s00249-005-0016-8
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DOI: https://doi.org/10.1007/s00249-005-0016-8