Grant: Project Grant

Protein synthesis plays a central role in regulating information flow in all cells of all organisms. Our research program studies a key regulator of the protein synthesis pathway - a complex referred to as eukaryotic initiation factor (eIF) 4F. Fine tuning of eIF4F activity in cells is critical to the correct execution of numerous biological processes - ranging from cell division, proliferation, differentiation, response to infection, metabolism, and to the higher brain functions of memory and learning. The activity of eIF4F is deregulated in the majority (>70%) of human cancers where it fuels tumor initiation, progression and promotes drug resistance. The consequences of altered eIF4F activity are to engender changes in the types and levels of proteins synthesized, which in turn fosters the growth and survival needs of an emerging or resident tumor cell. As well, mRNA therapeutics such as the SARS-CoV-2 vaccine must be able to efficiently interact with eIF4F to maximize protein output during immunization. Our understanding of eIF4F activity is quite rudimentary. We know of the existence of at least eight different eIF4F complexes in mammals, yet to date, the biochemical activity of only one of these has been extensively studied. The goal of the current proposal is to use chemical, biochemical, and structural biology approaches to better understand the role that the different eIF4F complexes play in determining protein levels in cells. We will produce the eight different eIF4F complexes for biochemical characterization, assess their ability to stimulate protein production, determine the structure of the best characterized eIF4F complex, and define the set of mRNAs that are responsive to each different eIF4F subunit. Our work will provide critical insight into features that determine mRNA responsiveness to different eIF4F complexes - fundamental information that is needed for optimal development of NexGen mRNA therapeutics.