ArticleeLife2020
Uncovering the basis of protein-protein interaction specificity with a combinatorially complete library.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed.
- Sequence-free landscape inference for directed evolution.PLoS computational biology · 2026Article
- Inference of fitness landscapes with heterogeneous patterns of epistasis across sites.bioRxiv : the preprint server for biology · 2026Article
- Phosphorylation of PfiA modulates Pf4 phage production through PfiA/PfiT stoichiometric reconfiguration inScience advances · 2026Article
- Efficient, Few-shot Directed Evolution with Energy Rank Alignment.bioRxiv : the preprint server for biology · 2026Article
- Inference and Visualization of Complex Genotype-Phenotype Maps.Molecular biology and evolution · 2026Article
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.Nature ecology & evolution · 2025Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Article
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.bioRxiv : the preprint server for biology · 2025Article
- Understanding the physiological role and cross-interaction network of VapBC35 toxin-antitoxin system from Mycobacterium tuberculosis.Communications biology · 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
- Antibody-based alternatives to animal testing for toxin detection and antitoxin evaluation.Frontiers in toxicology · 2025Review
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.bioRxiv : the preprint server for biology · 2024Article
- The genetic architecture of protein interaction affinity and specificity.Nature communications · 2024Article
- The simplicity of protein sequence-function relationships.Nature communications · 2024Article
- Machine learning-guided co-optimization of fitness and diversity facilitates combinatorial library design in enzyme engineering.Nature communications · 2024Article
- Following the Evolutionary Paths of Dscam1 Proteins toward Highly Specific Homophilic Interactions.Molecular biology and evolution · 2024Article
- Article
- Genotype sampling for deep-learning assisted experimental mapping of a combinatorially complete fitness landscape.Bioinformatics (Oxford, England) · 2024Article
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Authors and funding
6 authors.
Funding
Abstract
Protein-protein interaction specificity is often encoded at the primary sequence level. However, the contributions of individual residues to specificity are usually poorly understood and often obscured by mutational robustness, sequence degeneracy, and epistasis. Using bacterial toxin-antitoxin systems as a model, we screened a combinatorially complete library of antitoxin variants at three key positions against two toxins. This library enabled us to measure the effect of individual substitutions on specificity in hundreds of genetic backgrounds. These distributions allow inferences about the general nature of interface residues in promoting specificity. We find that positive and negative contributions to specificity are neither inherently coupled nor mutually exclusive. Further, a wild-type antitoxin appears optimized for specificity as no substitutions improve discrimination between cognate and non-cognate partners. By comparing crystal structures of paralogous complexes, we provide a rationale for our observations. Collectively, this work provides a generalizable approach to understanding the logic of molecular recognition.
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Registered trials
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