Investigating the properties of the ribosomes and their impact on translation dynamics across scales and systems

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The translation of mRNA into protein is a fundamental, yet complex biological process, mediated by ribosomes. To explain what can affect its efficiency, it is crucial to unravel the interactions between the ribosomes and other molecular complexes, but also to take into account other factors at a larger scale. The main goal of this proposal is to draw a global picture of the role played by ribosomes in translational systems across different scales, encompassing molecular, cellular and evolutionary aspects. More specifically, I will investigate 1) the biophysical properties and evolution of the ribosome exit tunnel, 2) different modes of translation, transport and remodeling of the ribosome in response to specific spatial cellular organizations and 3) the limiting factors that drive protein translation at the system level. These complementary approaches will both elucidate the functional impact of the ribosome structure, and conversely, determine how spatial or resources management impose evolutionary and design constraints at the molecular level. I will analyze the biophysical properties of the exit tunnel from cryo EM data, and elucidate the interplay between the tunnel electrostatics and geometry. These biophysical properties will also be studied in the context of evolution, with cryo EM structures of the ribosomes available for many species. Studying the evolution of the ribosome and its tunnel will require inferring ancestral shapes that can potentially explain different modes of translation. At the mesoscopic scale, we will focus on two important modes of translation: First, the translation of membrane protein genes, which involves transport to the endoplasmic reticulum (ER). Interestingly, this gives rise to geometric patterns of polyribosomes on the ER membrane. To explain these patterns, we will study a new biophysical model of translation, and compare the patterns with imaging data. The second local mode of translation to investigate occurs in dendritic regions, located far from the cell nucleus. By combining theoretical analysis of modes of transport, with differential expression data, we will build statistical tools to distinguish, for different genes, their mode of transport, and infer the associated local translation dynamics. At the system scale, we are interested in the metabolic cost of translation. In vitro time-series measurements of protein levels plateau, with multiple potential limiting factors. Upon fitting a mathematical model to various experimental conditions, I will disentangle the contribution of these factors. This modeling approach will serve as a first step for high-throughput measurement of translation rates. In vivo, living systems also need to manage the ribosomal population. In particular, "ribophagy" pathway can not only decrease the ribosomal pool, but also allows the recycling of ribosomal components. To assess the robustness and optimality of this pathway, I will use optimal control.