Cell Systems
Volume 7, Issue 6, 26 December 2018, Pages 580-589.e4
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Article
Production of Protein-Complex Components Is Stoichiometric and Lacks General Feedback Regulation in Eukaryotes

https://doi.org/10.1016/j.cels.2018.11.003Get rights and content
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Highlights

  • Improved estimate of protein synthesis using authentic ribosome footprint density

  • Nearly all protein complexes in yeast are made in proportion to their stoichiometry

  • Large protein complexes in higher eukaryotes follow proportional synthesis

  • Proportional synthesis is not maintained by feedback regulation for most complexes

Summary

Constituents of multiprotein complexes are required at well-defined levels relative to each other. However, it remains unknown whether eukaryotic cells typically produce precise amounts of subunits, or instead rely on degradation to mitigate imprecise production. Here, we quantified the production rates of multiprotein complexes in unicellular and multicellular eukaryotes using ribosome profiling. By resolving read-mapping ambiguities, which occur for a large fraction of ribosome footprints and distort quantitation accuracy in eukaryotes, we found that obligate components of multiprotein complexes are produced in proportion to their stoichiometry, indicating that their abundances are already precisely tuned at the synthesis level. By systematically interrogating the impact of gene dosage variations in budding yeast, we found a general lack of negative feedback regulation protecting the normally precise rates of subunit synthesis. These results reveal a core principle of proteome homeostasis and highlight the evolution toward quantitative control at every step in the central dogma.

Keywords

proportional synthesis
proteome homeostasis
feedback regulation
ribosome profiling
dosage compensation

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