ArticleProceedings of the National Academy of Sciences of the United States of America2012
Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 64 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
64 citing papers in PubMed.
- Novel truncating Desmin mutation Arg150Stop disrupts structural integrity and cellular homeostasis by formation of persistent aggregate-like structure.Cell death discovery · 2026Article
- Structural modeling and docking analysis of canonical and novel resistance-associated missense mutations in Sudanese Escherichia coli.Scientific reports · 2026Article
- Simple genetic mechanisms toward more intricate molecular complexes.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.Nature communications · 2024Article
- Resolving chaperone-assisted protein folding on the ribosome at the peptide level.Nature structural & molecular biology · 2024Article
- Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.bioRxiv : the preprint server for biology · 2024Article
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- Empowering drug off-target discovery with metabolic and structural analysis.Nature communications · 2023Article
- Fitness and Functional Landscapes of the E. coli RNase III Gene rnc.Molecular biology and evolution · 2023Article
- Intra-Frontiers in genetics · 2023Article
- Enhancing computational enzyme design by a maximum entropy strategy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Switching an active site helix in dihydrofolate reductase reveals limits to subdomain modularity.Biophysical journal · 2021Article
- Development of antibacterial compounds that constrain evolutionary pathways to resistance.eLife · 2021Article
- Avoidance of protein unfolding constrains protein stability in long-term evolution.Biophysical journal · 2021Article
- Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype.Molecular systems biology · 2021Article
- Collateral fitness effects of mutations.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural and dynamic origins of ESR lineshapes in spin-labeled GB1 domain: the insights from spin dynamics simulations based on long MD trajectories.Scientific reports · 2020Article
- Article
- Chimeric dihydrofolate reductases display properties of modularity and biophysical diversity.Protein science : a publication of the Protein Society · 2019Article
- High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection.Molecular biology and evolution · 2019Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedWu, Wanmeng [corrected to Mu, Wanmeng]
Authors and funding
4 authors.
Funding
Abstract
Mutations create the genetic diversity on which selective pressures can act, yet also create structural instability in proteins. How, then, is it possible for organisms to ameliorate mutation-induced perturbations of protein stability while maintaining biological fitness and gaining a selective advantage? Here we used site-specific chromosomal mutagenesis to introduce a selected set of mostly destabilizing mutations into folA--an essential chromosomal gene of Escherichia coli encoding dihydrofolate reductase (DHFR)--to determine how changes in protein stability, activity, and abundance affect fitness. In total, 27 E. coli strains carrying mutant DHFR were created. We found no significant correlation between protein stability and its catalytic activity nor between catalytic activity and fitness in a limited range of variation of catalytic activity observed in mutants. The stability of these mutants is strongly correlated with their intracellular abundance, suggesting that protein homeostatic machinery plays an active role in maintaining intracellular concentrations of proteins. Fitness also shows a significant correlation with intracellular abundance of soluble DHFR in cells growing at 30 °C. At 42 °C, the picture was mixed, yet remarkable: A few strains carrying mutant DHFR proteins aggregated, rendering them nonviable, but, intriguingly, the majority exhibited fitness higher than wild type. We found that mutational destabilization of DHFR proteins in E. coli is counterbalanced at 42 °C by their soluble oligomerization, thereby restoring structural stability and protecting against aggregation.
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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.