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Abstract
Author SummaryThe biophysical properties of proteins must adjust to accommodate environmental temperatures because of the narrow range over which any given protein sequence can remain folded and functional. We compared the evolution of homologous bacterial enzymes (ribonucleases H1) from two lineages: one from Escherichia coli, which live at moderate temperatures, the other from Thermus thermophilus, which live at extremely high temperatures. Our aim was to investigate how these structurally homologous proteins can have such different thermostabilities, unfolding at temperatures that are 20°C apart. We used bioinformatics to reconstruct the sequences of ancestral proteins along each lineage, synthesized the proteins in the lab, and experimentally traced the evolution of ribonuclease H1 stability. While thermostability appears to have been strongly shaped by selection, the biophysical mechanisms used to tune protein stability appear to have varied throughout evolutionary history; this suggests that proteins have wide latitude to explore different mechanisms of stabilization, generating biophysical diversity and opening up new evolutionary pathways.
Highlights
Protein thermostability is almost certainly tuned by natural selection
There are good theoretical reasons to believe that natural selection, but not neutral drift, can lead to a sustained increase in Tm: because random amino acid substitutions tend to decrease protein stability, the final Tm of a protein is expected to be the result of a balance between selection to maintain adequate stability and mutational pressure that drives stability downward [3]
We compared the evolution of homologous bacterial enzymes from two lineages: one from Escherichia coli, which live at moderate temperatures, the other from Thermus thermophilus, which live at extremely high temperatures
Summary
Protein thermostability is almost certainly tuned by natural selection. The fold of a protein is sensitive to denaturation at high temperatures: above the melting temperature (Tm) proteins lose structure, function, and become prone to aggregation. Detailed comparisons of mesophilic and thermophilic homologs have revealed many differences that increase Tm, such as novel interactions in the folded state and residual structure in the unfolded state. These underlying biophysical differences, and the sequence differences that encode them, are usually interpreted as the direct product of selection during adaption to hightemperature environments [5,6]. Such narratives regarding natural selection, are essentially ‘‘just-so’’ stories with little or no empirical justification [7]: many of the mechanistic
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