title: Protein misinteraction avoidance causes highly expressed proteins to evolve slowly.
abstract: 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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Yang
authors.forename: Ben-Yang
authors.initials: BY
authors.lastname: Liao
authors.forename: Shi-Mei
authors.initials: SM
authors.lastname: Zhuang
authors.forename: Jianzhi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D019418:Evolution, Chemical; D016681:Genome, Fungal; D011485:Protein Binding; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins