ArticleProceedings of the National Academy of Sciences of the United States of America2011
Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 171 papers.
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Who cites it
171 citing papers in PubMed, 323 citations in OpenAlex.
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- Engineering a robust cell-surface display platform in the multi-stress-tolerant yeast Issatchenkia orientalis.Applied microbiology and biotechnology · 2026Article
- Environmental and mutational modulation of collateral fitness effects informs their mechanisms.Molecular biology and evolution · 2026Article
- Yeast Stress Response to Synthetic Constructs.ACS synthetic biology · 2026Review
- Contrasting pH optima of β-lactamases CTX-M and CMY influenceApplied and environmental microbiology · 2026Article
- Unstressed cells are alike, but stressed cells differ: Environmental and single-cell heterogeneity in yeast stress responses.bioRxiv : the preprint server for biology · 2026Article
- Mutation-induced filaments of folded proteins are inert and non-toxic in a cellular system.Molecular systems biology · 2025Article
- Metabolic engineering of Saccharomyces cerevisiae for neoxanthin production.Microbial cell factories · 2025Article
- A Conserved N-Terminal Di-Arginine Motif Stabilizes Plant DGAT1 and Modulates Lipid Droplet Organization.International journal of molecular sciences · 2025Article
- In silico evolution of globular protein folds from random sequences.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Effects of Sup35 overexpression on the formation, morphology, and physiological functions of intracellular Sup35 assemblies.Applied and environmental microbiology · 2025Article
- Dominant negative mutations in yeast Hsp90 indicate triage decision mechanism targeting client proteins for degradation.Molecular biology of the cell · 2025Article
- Genome-wide impact of codon usage bias on translation optimization in Drosophila melanogaster.Nature communications · 2024Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.eLife · 2024Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.bioRxiv : the preprint server for biology · 2024Article
- Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation.bioRxiv : the preprint server for biology · 2024Article
- An adaptive biomolecular condensation response is conserved across environmentally divergent species.Nature communications · 2024Article
- Agglomeration: when folded proteins clump together.Biophysical reviews · 2023Review
- Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast.Nature chemical biology · 2023Article
- A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.Molecular cell · 2023Article
111 more citing papers are in PubMed but not listed here.
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6 authors at 2 institutions in 1 country.
Funding
Abstract
Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine-5'-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.