Stanley, RJ;
(2015)
Mathematical models of signalling through G proteins and phospholipids.
Doctoral thesis , UCL (University College London).
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Abstract
G proteins and phospholipids are two major classes of signalling molecule. ey are each—independently and together—involved in diverse ‘signalling pathways’ – bio- chemical networks through which cells maintain healthy responses to stimuli. A unique ‘cross-talk motif’ is formed by regulation of the phospholipid-modifying enzymes phospholipase D (PLD) and phosphatidylinositol 4-phosphate 5-kinase (PI4P5K) by the Arf family of small G proteins and—curiously—each other’s product. Here, understanding of this inherently complex motif has been strengthened by the development and analysis of mathematical models, specifically systems of ordinary differential equations (ODEs). Construction of simple empirical models suggests asymmetry in the mechanisms of regulation of the enzymes is responsible for production of two distinct outgoing signals from a single input signal, one displaying threshold activation behaviour. Additionally, well-defined quasi-steady-state (QSS) mechanistic models (à la Michaelis- Menten) have been developed for each of: PLD; PI4P5K; and G protein/Arf regula- tion. During this process—due to insufficient pre-existing descriptions—biochemically- plausible assumptions were required for certain regulatory and catalytic interactions. Analysis of the G protein regulation models establishes that—contrary to previous representations—this regulation is best described by a balance/unbalance mechanism, where observed activation absolutely requires the presence of the inactivator. Together, the QSS models can be combined to form a complete model of the Arf/PLD/ PI4P5K motif suitable for computational simulation – preliminary parameters show that this model is capable of displaying physiologically-plausible behaviours ese results give a be er understanding of the signalling role of the Arf/PLD/PI4P5K motif; lead to novel biological hypotheses amenable to later experimental validation; highlight where our current biological understanding of the system is insufficient; and suggest novel methods for the therapeutic control of G proteins.
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