ArticlePLoS genetics2013
Mechanisms of protein sequence divergence and incompatibility.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed.
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Analysing a Group of Homologous BAHD Enzymes Provides Insights into the Evolutionary Transition of Rosmarinic Acid Synthases from Hydroxycinnamoyl-CoA:Shikimate/Quinate Hydroxycinnamoyl Transferases.Plants (Basel, Switzerland) · 2024Article
- Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance.eLife · 2022Article
- SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: A Computational Model of Epitope Loss in Variants of Concern.Journal of chemical information and modeling · 2021Article
- Amino acid impact factor.PloS one · 2018Article
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- Evaluating Functional Annotations of Enzymes Using the Gene Ontology.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Antibiotic resistance evolved via inactivation of a ribosomal RNA methylating enzyme.Nucleic acids research · 2016Article
- Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein.PLoS genetics · 2016Article
- SHV-129: A Gateway to Global Suppressors in the SHV β-Lactamase Family?Molecular biology and evolution · 2016Article
- Residue proximity information and protein model discrimination using saturation-suppressor mutagenesis.eLife · 2015Article
- Handicap-Recover Evolution Leads to a Chemically Versatile, Nucleophile-Permissive Protease.Chembiochem : a European journal of chemical biology · 2015Article
- Reverse evolution leads to genotypic incompatibility despite functional and active site convergence.eLife · 2015Article
- Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations.PLoS computational biology · 2015Article
- Insights into the evolution of enzyme substrate promiscuity after the discovery of (βα)₈ isomerase evolutionary intermediates from a diverse metagenome.BMC evolutionary biology · 2015Article
- Emergence of terpene cyclization in Artemisia annua.Nature communications · 2015Article
- A model of substitution trajectories in sequence space and long-term protein evolution.Molecular biology and evolution · 2015Article
- Article
- The Valley-of-Death: reciprocal sign epistasis constrains adaptive trajectories in a constant, nutrient limiting environment.Genomics · 2014Article
- A structural perspective of compensatory evolution.Current opinion in structural biology · 2014Review
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3 authors.
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Abstract
Alignments of orthologous protein sequences convey a complex picture. Some positions are utterly conserved whilst others have diverged to variable degrees. Amongst the latter, many are non-exchangeable between extant sequences. How do functionally critical and highly conserved residues diverge? Why and how did these exchanges become incompatible within contemporary sequences? Our model is phosphoglycerate kinase (PGK), where lysine 219 is an essential active-site residue completely conserved throughout Eukaryota and Bacteria, and serine is found only in archaeal PGKs. Contemporary sequences tested exhibited complete loss of function upon exchanges at 219. However, a directed evolution experiment revealed that two mutations were sufficient for human PGK to become functional with serine at position 219. These two mutations made position 219 permissive not only for serine and lysine, but also to a range of other amino acids seen in archaeal PGKs. The identified trajectories that enabled exchanges at 219 show marked sign epistasis - a relatively small loss of function with respect to one amino acid (lysine) versus a large gain with another (serine, and other amino acids). Our findings support the view that, as theoretically described, the trajectories underlining the divergence of critical positions are dominated by sign epistatic interactions. Such trajectories are an outcome of rare mutational combinations. Nonetheless, as suggested by the laboratory enabled K219S exchange, given enough time and variability in selection levels, even utterly conserved and functionally essential residues may change.
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