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Abstract

Contemporary proteins arose by combinatorial shuffling and differentiation from a basic set of domain prototypes, most of which were already established at the time of the Last Universal Common Ancestor (LUCA), 3.5 billion years ago. The origin of domains themselves, however, is poorly understood. We are pursuing the hypothesis that they arose by fusion, accretion, and repetition from an ancestral set of peptides active as co-factors of RNA-dependent replication and catalysis (the 'RNA world'). We reasoned that if this hypothesis is true, comparative studies should allow a description of this peptide set. To this end, we compared domains representative of known folds and identified 40 fragments that occur in domains of different folds, yet show significant similarities in sequence and structure. Based on their widespread occurrence in the most ancient folds (e.g. the P-loop NTPases and ribosomal proteins) and on their involvement in basal functions (e.g. nucleic acid-binding and metal-binding), we propose that these fragments represent the observable remnants of a primordial RNA-peptide world.