Mathematical Modelling of Inter- and Intracellular Signal Transduction: The Regulatory Role of Multisite Interactions

Abstract

Signalling processes regulate various aspects of living cells via modulation of protein activity. The interactions between the signalling proteins can occur at single or multiple sites. Although single site protein interactions are relatively easy to understand, these rarely occur in living systems. It is therefore important to investigate multisite interactions. Despite the recent progress in experimental studies, the underlying molecular mechanisms and molecular functions of the multisite interactions are still not clear and therefore require systems approaches for deeper understanding, for example to understand how the system will react to perturbation of one of its components. The examples of the molecular functions that are studied in this thesis are: kinetics of multisite calcium binding to proteins such as calmodulin (CaM), multisite phosphorylation of interferon regulatory factor 5 (IRF-5) and signal transducers and activators of transcription (STATs). We also study the role of STATs in the overall immune response and in T cell phenotype switching as well as multisite phosphorylation of high osmolarity glycerol factor 1 (Hog1) in mitogen activated protein kinase (MAPK) cascade during the adaptation of Candida glabrata to osmotic stress. In this thesis, these examples are studied using the systems approach in the context of human diseases: cancer, candidiasis, immunity-related pathologies such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. We discuss potential therapeutic implications of the proposed models in these diseases. The predictions of the models developed in this thesis are supported by the experimental data and propose possible mechanisms of the multisite interactions involved in the cellular regulation.