Abstract
Abstract
Refined by more than three billion years of evolution, thousands of proteins govern most of the diverse structural and functional features of today’s cells. Although the alphabet of today’s proteins consists of 20 amino acids, highly functional molecules can be constructed out of a subset of these, and this was most certainly the case at the dawn of the protein world. A major challenge for proteins is the rapid attainment of proper structures by folding into stable subunits, which when exceeding 250 residues in length, requires the assistance of chaperones. Fewer than 25% of amino acid-altering mutations are accepted in nature, and of those that do survive, most have very small effects and can be guided by mutation bias. Despite their high levels of refinement, most proteins have catalytic rates and folding stabilities far below the limits set by biophysical constraints, suggesting a barrier imposed by random genetic drift. The stringency of selection is elevated for protein-coding genes with high levels of expression, as these incur relatively high investment costs and, when mistranslated, are most likely to engage in harmful protein–protein interactions. Although often nearly neutral with respect to fitness, acceptable amino-acid exchanges commonly alter protein features in subtle ways that dictate the future mutations that can be fixed at other positions. As a consequence, protein-sequence evolution is often dominated by compensatory remodelling changes that, in retrospect, appear to involve strong and essential epistatic interactions, but nonetheless had accumulated in a nearly neutral fashion.
Publisher
Oxford University PressOxford
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