Saturday, November 23, 2024
11/23/2024
Project Summary/Abstract The proteome is a quantitative output of a genome and the ultimate effector of cellular functions. Yet remarkably little is known about the logic behind proteome construction. The goal of my research program is to understand the evolutionary driving forces and the molecular processes that shape protein levels in living cells. Using bacterial model systems, my lab takes a holistic approach by developing quantitative technologies to measure, manipulate, and model the expression stoichiometry of co-regulated proteins and the effect of imbalanced production on bacterial growth, survival, and colonization. This current grant seeks to answer several fundamental questions regarding the physiology and regulation of protein stoichiometry. At the physiological level, we use molecular and theoretical methods to determine 1) the optimality of protein production rates for every gene and the cellular responses to non-optimal levels, 2) the precise ratios of protein production upon sudden environmental changes and the consequences of imbalanced production, and 3) the theoretical basis for the stoichiometry of proteins that function together. These studies will help elucidate new principles for building a proteome and provide a new way of thinking about protein imbalance in disease. To understand the regulatory principles of gene expression behind this stoichiometric protein production, we use quantitative and massively parallel assays to determine 1) the sequence determinant of Rho- dependent transcription termination in Bacillus subtilis, whose RNAP polymerases outpace ribosomes (`runaway transcription'), 2) the molecular basis of runaway transcription, 3) a predictive model for the efficiency of Rho-independent transcription termination, and 4) the landscape of translational control for bacteriophage mRNAs. Our studies in these areas will help establish a critically needed framework for predicting gene expression from genomic sequences and advance fundamental knowledge of bacterial gene regulation. We anticipate that our mechanistic dissection, coupled with systems-level inquiry into proteome composition, will make bacterial model organisms the first system for which we have a quantitative understanding of the interplay between genome, proteome, and fitness.
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