Proteins share similar sequence segments with one another. Such 'reuse of parts' has clear evolutionary advantage over ‘design from scratch', which often generates segments that cannot even fold, let alone be active. The best characterized form of reuse involves ‘domains’, where the shared segments are of 100 amino acids on average. It is, however, conceivable, that proteins reuse even smaller segments. If so, such segments can be regarded as the basic evolutionary units of proteins. To study this eventuality, we searched among two large and representative sets of proteins (~15,000 domains and ~20,000 full chains) for elongated amino acid segments that are similar in sequence and structure. We presented the results as a similarity network, where the proteins/domains were shown as nodes, and the edges connected proteins/domains that are similar, i.e., evolutionarily related. Indeed, this network view showed that protein space features a large connected component of domains that share smaller segments with each other, as well as many isolated ‘islands’, each corresponding to specific architecture. We observed reuse of amino acid segments of variable lengths, and called the reused parts ‘<i>themes</i>’ (as in ‘variations on a theme’). Very complex patterns emerged, where the same amino acid can appear both within a short reused theme, shared by many proteins, or within a longer theme, shared by few. Interestingly, some of the themes are found in domains that are considered ancient, e.g., Rossmann and P-loop enzymes, suggesting that they played a role in early events in the emergence of proteins in evolution. Further evidence to this end is that some themes mediate interactions with ancient ligands like iron-sulfur clusters and adenine. Overall, our studies suggest a recursive model of protein evolution, in which themes of various lengths, typically smaller than domains, ‘hop’ between contexts, and those that are fit remain, leaving traces for us to detect.

Protein archeology: How proteins emerged and evolve?

ACS Spring 2022

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