title: Fitness costs of minimal sequence alterations causing protein instability and toxicity.
abstract: Destabilization of a protein impairs its metabolic efficiency. It is less clear how often destabilization also results in a gain of toxicity. We derived collections of temperature-sensitive, and thus structurally unstable, mutants of the yeast ADE2 and LYS2 genes by introducing single or very few amino acids substitutions. Overexpression of these mutant proteins led to a common, although unequal, fitness decrease. Interestingly, although the mutant proteins were functionally redundant, higher expression levels were associated with higher fitness. This result suggests that growth was hampered not by the accumulation of damaged chains but by the activities needed to remove them or by the damage caused before they were removed. Our results support the idea that any protein can become toxic when destabilized by a point mutation.
authors.affiliation: Institute of Environmental Sciences, Jagiellonian University, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tomala
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pogoda
authors.forename: Agata
authors.initials: A
authors.lastname: Jakubowska
authors.forename: Ryszard
authors.initials: R
authors.lastname: Korona
mesh_terms: D001483:Base Sequence; D056084:Genetic Fitness; D050505:Mutant Proteins / Q000633:toxicity*; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D029701:Saccharomyces cerevisiae Proteins
keywords: Saccharomyces cerevisiae; fitness cost; thermal sensitivity