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.
Highlights
The origin of most present-day proteins can be attributed to combinatorial shuffling and differentiation events involving a basic set of domain prototypes, which act as the unit of protein evolution (Anantharaman et al, 2001; Apic et al, 2001; Ponting and Russell, 2002; Orengo and Thornton, 2005)
Many lines of evidence, including the identification of local sequence and structure similarity within domains of different fold (Brennan and Matthews, 1989; Doherty et al, 1996; Copley et al, 2001; Grishin, 2001b; Friedberg and Godzik, 2005; Alva et al, 2007; Andreeva et al, 2007), or the frequent construction of domains by repetition of subdomain-sized fragments (McLachlan, 1987; Andrade et al, 2001; Hocker et al, 2002; Chaudhuri et al, 2008; Remmert et al, 2010), show that domains might not constitute the only evolutionary unit of protein structure. These observations led to the proposal that the first folded domains arose by repetition, fusion, recombination, and accretion from an ancestral set of peptides (Fetrow and Godzik, 1998; Lupas et al, 2001; Soding and Lupas, 2003) that emerged in the RNA world (Gilbert, 1986), in which RNA served both as carrier of genetic information and catalyst of metabolic reactions (Jeffares et al, 1998)
Paralogous functions arose around the time of the Last Universal Common Ancestor from its ability to form a biotin-binding domain by duplication, yielding the biotin-dependant enzymes of the barrelsandwich hybrid fold, and to serve as a structural element in domains formed by accretion, yielding a domain of RNA-polymerase b’ subunit, as well as a range of enzymes with an a/b-hammerhead fold
Summary
The origin of most present-day proteins can be attributed to combinatorial shuffling and differentiation events involving a basic set of domain prototypes, which act as the unit of protein evolution (Anantharaman et al, 2001; Apic et al, 2001; Ponting and Russell, 2002; Orengo and Thornton, 2005). To reconstruct the ‘vocabulary’ of ancient peptides, we aimed at finding local similarities in sequence and structure within globally different folds, which are presently thought to have arisen independently, by convergent evolution. Since the comparisons made in the analogous set were between domains of different fold, the high-scoring matches always involved subdomain-sized fragments.
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