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• W2588507788 endingPage "1251" @default.
• W2588507788 startingPage "1240" @default.
• W2588507788 abstract "If the fitness effects of amino acid mutations are conditional on genetic background, then mutations can have different effects depending on the sequential order in which they occur during evolutionary transitions in protein function. A key question concerns the fraction of possible mutational pathways connecting alternative functional states that involve transient reductions in fitness. Here we examine the functional effects of multiple amino acid substitutions that contributed to an evolutionary transition in the oxygenation properties of avian hemoglobin (Hb). The set of causative changes included mutations at intradimer interfaces of the Hb tetramer. Replacements at such sites may be especially likely to have epistatic effects on Hb function since residues at intersubunit interfaces are enmeshed in networks of salt bridges and hydrogen bonds between like and unlike subunits; mutational reconfigurations of these atomic contacts can affect allosteric transitions in quaternary structure and the propensity for tetramer–dimer dissociation. We used ancestral protein resurrection in conjunction with a combinatorial protein engineering approach to synthesize genotypes representing the complete set of mutational intermediates in all possible forward pathways that connect functionally distinct ancestral and descendent genotypes. The experiments revealed that 1/2 of all possible forward pathways included mutational intermediates with aberrant functional properties because particular combinations of mutations promoted tetramer–dimer dissociation. The subset of mutational pathways with unstable intermediates may be selectively inaccessible, representing evolutionary roads not taken. The experimental results also demonstrate how epistasis for particular functional properties of proteins may be mediated indirectly by mutational effects on quaternary structural stability." @default.
• W2588507788 created "2017-02-24" @default.
• W2588507788 creator A5026872382 @default.
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• W2588507788 creator A5066695173 @default.
• W2588507788 creator A5070118734 @default.
• W2588507788 creator A5071074398 @default.
• W2588507788 date "2017-02-13" @default.
• W2588507788 modified "2023-10-17" @default.
• W2588507788 title "Stability-Mediated Epistasis Restricts Accessible Mutational Pathways in the Functional Evolution of Avian Hemoglobin" @default.
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• W2588507788 doi "https://doi.org/10.1093/molbev/msx085" @default.
• W2588507788 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5400398" @default.

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