A vocabulary of ancient peptides at the origin of folded proteins

Abstract

The seemingly limitless diversity of proteins in nature arose from only a few thousand domain prototypes, but the origin of these themselves has remained unclear. We are pursuing the hypothesis that they arose by fusion and accretion from an ancestral set of peptides active as co-factors in RNA-dependent replication and catalysis. Should this be true, contemporary domains may still contain vestiges of such peptides, which could be reconstructed by a comparative approach in the same way in which ancient vocabularies have been reconstructed by the comparative study of modern languages. To test this, we compared domains representative of known folds and identified 40 fragments whose similarity is indicative of common descent, yet which occur in domains currently not thought to be homologous. These fragments are widespread in the most ancient folds and enriched for iron-sulfur- and nucleic acid-binding. We propose that they represent the observable remnants of a primordial RNA-peptide world.Life as we know it today is largely the result of the chemical activity of proteins. Much research suggests that the ancestors for most modern proteins were already present in the ‘Last Universal Common Ancestor’, a theoretical ancient organism from which all life on earth descended and which lived around 3.5 billion years ago.Today, related versions of these ancestral proteins are found in organisms as different as bacteria, humans and plants. While they seem highly diverse, these proteins were all assembled from only a few thousand modular units, termed domains. However, it is not clear how the first domains emerged.Previously, in 2001 and 2003, researchers hypothesized that the first protein domains arose by joining and swapping short lengths of proteins called peptides that had emerged before there were living cells on earth – a time that is often called the “RNA world”. Now, Alva et al. – including the researchers involved in the 2003 work – have attempted to detect remnants of these ancient peptides in modern proteins.Alva et al. first compared modern proteins in a way that is similar to how linguists have compared modern languages to reconstruct ancient vocabularies. This revealed 40 fragments that occur in seemingly unrelated proteins, but are very similar in their sequence and structure. These fragments are commonly found in what are likely the oldest observable proteins, and are involved in the activities that are most fundamental to life (for example, binding to DNA and RNA). This led Alva et al. to propose that these fragments represent the observable remnants of a primordial “RNA-peptide world”.The hypothesis that proteins evolved from peptides provides a number of predictions that can be tested in experiments. These fragments open avenues to explore in the laboratory the origin of modern proteins and to build new proteins not seen in nature.