Abstract
Enzymatic pathways have evolved uniquely preferred protein expression stoichiometry in living cells, but our ability to predict the optimal abundances from basic properties remains underdeveloped. Here, we report a biophysical, first-principles model of growth optimization for core mRNA translation, a multi-enzyme system that involves proteins with a broadly conserved stoichiometry spanning two orders of magnitude. We show that predictions from maximization of ribosome usage in a parsimonious flux model constrained by proteome allocation agree with the conserved ratios of translation factors. The analytical solutions, without free parameters, provide an interpretable framework for the observed hierarchy of expression levels based on simple biophysical properties, such as diffusion constants and protein sizes. Our results provide an intuitive and quantitative understanding for the construction of a central process of life, as well as a path toward rational design of pathway-specific enzyme expression stoichiometry.
Highlights
A universal challenge faced by both evolution and synthetic pathway creation is to optimize the cellular abundance of proteins
Distinct proteins that evolved convergently towards the same biological function displayed the same stoichiometry of protein synthesis in their respective species
These results suggest that the determinants of optimal in-pathway protein stoichiometry are likely modular and independent of detailed biochemical or physiological properties that differ across clades
Summary
A universal challenge faced by both evolution and synthetic pathway creation is to optimize the cellular abundance of proteins. – often involving several proteins participating in the same pathway – and under systems-wide constraints, such as limited physical space (Klumpp et al, 2013) and finite nutrient inputs (You 25 et al, 2013) The complexity of this problem has prevented rational design of protein expression for 26 pathway engineering (Jeschek et al, 2017). Distinct proteins that evolved convergently towards the same biological function displayed the same stoichiometry of protein synthesis in their respective species. These results suggest that the determinants of optimal in-pathway protein stoichiometry are likely modular and independent of detailed biochemical or physiological properties that differ across clades.
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