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Abstract

Folded proteins are the essential catalysts of life, but the ability to fold is a rare, complicated, and easily disrupted property, whose emergence at the origin of life is poorly understood. We have proposed that folded proteins arose from an ancestral set of peptides that acted as cofactors of RNA-mediated catalysis and replication [1]. Initially, these peptides were entirely dependent on the RNA scaffold for their structure, but as their complexity increased, they became able to form structures by excluding water through hydrophobic contacts, making them independent of the RNA scaffold. Their ability to fold was thus an emergent property of peptide-RNA coevolution. The ribosome is the main survivor of this primordial RNA world. It’s very slow rate of change makes it an excellent model system for retracing the steps that led to the folded proteins of today [2]. Towards its center, proteins are extended and largely devoid of secondary structure; further out, their secondary structure content increases and supersecondary topologies become common, although the proteins still largely lack a hydrophobic core; at the ribosomal periphery, supersecondary structures coalesce around hydrophobic cores, forming folds that resemble those seen in proteins of the cytosol. Collectively, ribosomal proteins chart a path of progressive emancipation from the RNA scaffold, offering a window onto the time when proteins were acquiring the ability to fold. We retraced this emancipation for an αα-hairpin from ribosomal protein RPS20, which is unstructured in the absence of its cognate RNA, but which folds autonomously when repeated at least three times within the same polypeptide chain [3]. A global analysis of ribosomal proteins for fragments that could fold upon repetition or recombination shows that this is a wide-spread, albeit cryptic, property.