Networks of molecular regulators are often the primary objects of focus in the study of gene regulation, with the machinery of protein synthesis tacitly relegated to the background. Shifting focus to the constraints imposed by the allocation of protein synthesis flux reveals surprising ways in which the actions of molecular regulators are shaped by physiological demands. Using carbon catabolite repression as a case study, we describe how physiological constraints are sensed through metabolic fluxes and how flux-controlled regulation gives rise to simple empirical relations between protein levels and the rate of cell growth.
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This Review was shaped by extended discussion with numerous colleagues and collaborators over the years. It grew from early discussions with Eduard Mateescu and Stefan Klumpp, and with Hans Bremer, Lazlo Csonka, Antoine Danchin, Patrick Dennis, Peter Geiduschek, Sydney Kustu, Bill Loomis, Elio Schaechter, and Dalai Yan. Many insightful ideas came from colleagues whose proteomic data underlies the pie charts shown in the figures: Ruedi Aebersold, Gene-wei Li, Christina Ludwig, and especially Vadim Patsalo, Josh Silverman and Jamie Williamson. Our current understanding of proteome allocation constraints would not have been possible without the input of Rosalind Allen, Frank Bruggeman, Mans Ehrenberg, Suckjoon Jun, Meriem el Karoui, Karl Kochanowski, Martin Lercher, Fernanda Pinheiro, Uwe Sauer, Bas Teusink, Yiping Wang, and current and former members of the Hwa laboratory, especially Rohan Balakrishnan, Markus Basan, David Erickson, Tony Hui, Matteo Mori, Hiroyuki Okano, Severin Schink, Chenhao Wu, Conghui You and Zhongge Zhang. Support for the Hwa laboratory has been provided by the NIH (R01GM095903, R01GM109069), the NSF (PHY105873, MCB 1818384) and the Simons Foundation (330378). M.S. was supported by NSERC (2016-03658).
The authors declare no competing interests.
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- Anabolic enzymes
Enzymes responsible for biosynthesis, including amino acid and nucleotide synthesis.
- Carbon catabolic proteins
Proteins responsible for the transport and breakdown of extracellular carbon sources. Operationally, these are genes regulated by cAMP–Crp.
The negative correlation between catabolic enzyme expression and growth rate in minimal media when growth rate is modulated by carbon source.
- Diauxic growth
Multiple stages of exponential growth as carbon sources are preferentially utilized. The time to switch between carbon sources can take several hours.
- Nutrient quality
The exponential growth rate can be modulated by changing the carbon source or nitrogen source, or enriching the medium with amino acids and nucleotides.
- Per-total protein-mass abundance
The concentration constraint (biomass/cell water volume) allows a direct conversion between the concentration ((amount of a particular molecule)/(cell water volume)) and its abundance relative to total protein mass ((amount of a particular molecule)/(total protein mass)) assuming that the biomass contains a fixed fraction of protein.
- Protein density
The buoyant density ((biomass and water mass)/cell volume) is independent of the growth rate under isotonic conditions. A constant density constraint (biomass/cell volume) therefore implies a constant concentration constraint (biomass/cell water volume). The cellular volume has strong growth-rate dependence; consequently, we do not use protein-number-per-cell as an abundance measure in this Review.
- Protein mass fraction
The total number of a particular protein is proportional to its protein mass. Using the per-total protein-mass abundance defined above, the protein mass fraction (protein mass of a particular protein/total protein mass) is therefore a direct measure of concentration.
The set of all expressed proteins in a given growth condition.
- Proteome sectors
Subsets of the proteome that exhibit similar growth-rate dependence under various growth conditions.
The positive correlation between the abundance of protein-synthetic machinery (chiefly ribosomes) and growth rate when growth rate is modulated by nutrient quality.
- Unregulated protein
Protein expression not subject to any transcriptional or post-transcriptional regulation.
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Scott, M., Hwa, T. Shaping bacterial gene expression by physiological and proteome allocation constraints. Nat Rev Microbiol (2022). https://doi.org/10.1038/s41579-022-00818-6