ArticleProceedings of the National Academy of Sciences of the United States of America2017
Trade-offs between enzyme fitness and solubility illuminated by deep mutational scanning.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
97 citing papers in PubMed.
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Decoding the substrate specificity landscape of a promiscuous enzyme through multi-substrate mutational scanning.Nature communications · 2026Article
- The allosteric landscape of the Src kinase.Science advances · 2026Article
- Advances in Machine Learning Models for Predicting Enzyme Kinetic Parameters.Journal of chemical information and modeling · 2026Review
- Computational redesign of a thermostable T7 RNA polymerase.Protein engineering, design & selection : PEDS · 2026Article
- Examining selection dynamics and limitations in multi-round protein selection of high diversity libraries.Protein engineering, design & selection : PEDS · 2026Article
- AI-Driven Enzyme Engineering: Emerging Models and Next-Generation Biotechnological Applications.Molecules (Basel, Switzerland) · 2025Review
- Computational redesign of a thermostable T7 RNA polymerase.bioRxiv : the preprint server for biology · 2025Article
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- SAGE-prot: scoring-assisted generative exploration for multi-objective protein design.Briefings in bioinformatics · 2025Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- The Achilles Heel of Protein Biochemistry: Insolubility of Recombinant Proteins-A Case Study About Producing a Rice Enzyme.International journal of molecular sciences · 2025Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- Pervasive Divergence in Protein Thermostability is Mediated by Both Structural Changes and Cellular Environments.Molecular biology and evolution · 2025Article
- Deep mutational scanning reveals a de novo disulfide bond and combinatorial mutations for engineering thermostable myoglobin.Protein science : a publication of the Protein Society · 2025Article
- Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens.Cell chemical biology · 2025Review
- Anticipating protein evolution with successor sequence predictor.Journal of cheminformatics · 2025Article
- ProG-SOL: Predicting Protein Solubility Using Protein Embeddings and Dual-Graph Convolutional Networks.ACS omega · 2025Article
- Enzyme-substrate co-display on yeast empowers engineering of tobacco etch virus protease activity.Protein engineering, design & selection : PEDS · 2025Article
- Combining Oligo Pools and Golden Gate Cloning to Create Protein Variant Libraries or Guide RNA Libraries for CRISPR Applications.Methods in molecular biology (Clifton, N.J.) · 2025Article
37 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
Abstract
Proteins are marginally stable, and an understanding of the sequence determinants for improved protein solubility is highly desired. For enzymes, it is well known that many mutations that increase protein solubility decrease catalytic activity. These competing effects frustrate efforts to design and engineer stable, active enzymes without laborious high-throughput activity screens. To address the trade-off between enzyme solubility and activity, we performed deep mutational scanning using two different screens/selections that purport to gauge protein solubility for two full-length enzymes. We assayed a TEM-1 beta-lactamase variant and levoglucosan kinase (LGK) using yeast surface display (YSD) screening and a twin-arginine translocation pathway selection. We then compared these scans with published experimental fitness landscapes. Results from the YSD screen could explain 37% of the variance in the fitness landscapes for one enzyme. Five percent to 10% of all single missense mutations improve solubility, matching theoretical predictions of global protein stability. For a given solubility-enhancing mutation, the probability that it would retain wild-type fitness was correlated with evolutionary conservation and distance to active site, and anticorrelated with contact number. Hybrid classification models were developed that could predict solubility-enhancing mutations that maintain wild-type fitness with an accuracy of 90%. The downside of using such classification models is the removal of rare mutations that improve both fitness and solubility. To reveal the biophysical basis of enhanced protein solubility and function, we determined the crystallographic structure of one such LGK mutant. Beyond fundamental insights into trade-offs between stability and activity, these results have potential biotechnological applications.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.