Eukaryotic initiation factor 5 guanine-nucleotide dissociation inhibitor activity and control of translation initiation

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Interactions between proteins modulate essential functions, ensuring that organisms and their cells can grow and perform tasks at the correct time and place. Many proteins act together within complexes either with other proteins or also with other cell components (lipids, DNA or small molecules for example) to coordinate a common function. One group of proteins relevant to this proposal is required make (or synthesize) all new proteins in each cell in every organism. These are called 'protein synthesis factors'. Understanding how protein synthesis factors function and interact with each other is, therefore, fundamental to understanding how proteins are made in all cells, in all organisms. By improving our understanding how processes such as protein synthesis work in normal cells it can help scientists understand diseases in which this process is altered. From previous work done we know that defects in protein synthesis factors can be associated with a wide range of diseases in mammals such as forms of diabetes, obesity, or how infectious agents such as viruses are able to cause infections. Control of protein synthesis is also critical for organism responses to nutrient deprivation, stress, as a well as during embryo development including differentiation of tissues, for nervous system function including memory, and during the aging process. In work leading up to this proposal we identified a novel interaction between two protein synthesis factors known as eIF2 and eIF5 that is critical for protein synthesis regulation and describes a new function for the eIF5 protein. This work has defined a new step in the chain of events necessary for starting (or initiating) new rounds of protein synthesis. By discovering this new step, it has implications for how scientists understand the mechanisms of protein synthesis control. We now have a leading advantage, as we are the first researchers to uncover this. We propose here a set of detailed molecular experiments to characterise its role. Rather than using animals for this work, we will use purified systems in test tubes and perform some experiments in yeast cells which are an excellent cellular model system to study universal translational controls common to all forms of life. In addition to furthering our basic science knowledge, our findings may be directly relevant to several industries. For example, several new advanced medicines used to treat serious life-threatening diseases, or produce vaccines are proteins made specifically from different cell systems. Knowledge of our work could help maximize the production of each product, thereby helping to reduce costs of production.