ArticleNature ecology & evolution2022
Co-evolution of interacting proteins through non-contacting and non-specific mutations.
Article in Nature ecology & evolution, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 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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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- Integrative Genomic and Structural Analysis Reveals Diversity and Stability of yefM-yoeBCurrent microbiology · 2026Article
- Structural ontogeny of protein-protein interactions.Science (New York, N.Y.) · 2026Article
- Designing modular genetic sensors with TtgR/AcrR family transcriptional regulators by using a statistical and data-driven approach.Nucleic acids research · 2025Article
- Article
- Widespread epistasis shapes RNA polymerase II active site function and evolution.Nature communications · 2025Article
- Higher-order epistasis drives evolutionary unpredictability toward novel antibiotic resistance.bioRxiv : the preprint server for biology · 2025Article
- Evolutionary paths that link orthogonal pairs of binding proteins.Cell systems · 2025Article
- EvoWeaver: large-scale prediction of gene functional associations from coevolutionary signals.Nature communications · 2025Article
- High-throughput amino acid-level characterization of the interactions of plasminogen activator inhibitor-1 with variably divergent proteases.Protein science : a publication of the Protein Society · 2025Article
- Understanding the physiological role and cross-interaction network of VapBC35 toxin-antitoxin system from Mycobacterium tuberculosis.Communications biology · 2025Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.Nature communications · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- MMRT: MultiMut Recursive Tree for predicting functional effects of high-order protein variants from low-order variants.Computational and structural biotechnology journal · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.bioRxiv : the preprint server for biology · 2024Article
- Article
- Emergent time scales of epistasis in protein evolution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Higher-order epistasis within Pol II trigger loop haplotypes.bioRxiv : the preprint server for biology · 2024Article
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Machine learning-guided co-optimization of fitness and diversity facilitates combinatorial library design in enzyme engineering.Nature communications · 2024Article
- Article
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7 authors at 3 institutions in 1 country.
Funding
Abstract
Proteins often accumulate neutral mutations that do not affect current functions but can profoundly influence future mutational possibilities and functions. Understanding such hidden potential has major implications for protein design and evolutionary forecasting but has been limited by a lack of systematic efforts to identify potentiating mutations. Here, through the comprehensive analysis of a bacterial toxin-antitoxin system, we identified all possible single substitutions in the toxin that enable it to tolerate otherwise interface-disrupting mutations in its antitoxin. Strikingly, the majority of enabling mutations in the toxin do not contact and promote tolerance non-specifically to many different antitoxin mutations, despite covariation in homologues occurring primarily between specific pairs of contacting residues across the interface. In addition, the enabling mutations we identified expand future mutational paths that both maintain old toxin-antitoxin interactions and form new ones. These non-specific mutations are missed by widely used covariation and machine learning methods. Identifying such enabling mutations will be critical for ensuring continued binding of therapeutically relevant proteins, such as antibodies, aimed at evolving targets.
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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.