The tempo and mode of protein evolution have been central questions in biology. Genomic data have shown a strong influence of the expression level of a protein on its rate of sequence evolution (E-R anticorrelation), which is currently explained by the protein misfolding avoidance hypothesis. Here, we show that this hypothesis does not fully explain the E-R anticorrelation, especially for protein surface residues. We propose that natural selection against protein-protein misinteraction, which wastes functional molecules and is potentially toxic, constrains the evolution of surface residues. Because highly expressed proteins are under stronger pressures to avoid misinteraction, surface residues are expected to show an E-R anticorrelation. Our molecular-level evolutionary simulation and yeast genomic analysis confirm multiple predictions of the hypothesis. These findings show a pluralistic origin of the E-R anticorrelation and reveal the role of protein misinteraction, an inherent property of complex cellular systems, in constraining protein evolution.
|Evidence ID||Analyze ID||Interactor||Interactor Systematic Name||Interactor||Interactor Systematic Name||Type||Assay||Annotation||Action||Modification||Phenotype||Source||Reference||Note|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Gene Ontology Term||Gene Ontology Term ID||Qualifier||Aspect||Method||Evidence||Source||Assigned On||Annotation Extension||Reference|
|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Phenotype||Experiment Type||Experiment Type Category||Mutant Information||Strain Background||Chemical||Details||Reference|
|Evidence ID||Analyze ID||Regulator||Regulator Systematic Name||Target||Target Systematic Name||Experiment||Assay||Construct||Conditions||Strain Background||Reference|