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要旨

Life today depends entirely on proteins as catalysts, but this activityrotein Degradation targeting undruggables congressis dependent on the formation of defined three-dimensional structuresrotein Degradation targeting undruggables congress(folding). As only few randomly synthesized polypeptide chains haverotein Degradation targeting undruggables congressa folded structure, folding was clearly a major obstacle in the evo-rotein Degradation targeting undruggables congresslution of DNA-protein-based lifeforms from simpler precursor forms.rotein Degradation targeting undruggables congressWe have proposed that folded proteins resulted from the increasingrotein Degradation targeting undruggables congresscomplexity of a preselected, ancestral set of peptides, which supportedrotein Degradation targeting undruggables congressRNA-based life and required the RNA to assume their active confor-rotein Degradation targeting undruggables congressmation. A dominant mechanism to increase complexity is repetitionrotein Degradation targeting undruggables congressand we have attempted to recreate experimentally the path from anrotein Degradation targeting undruggables congressunstructured precursor to a folded protein by amplification. Specifi-rotein Degradation targeting undruggables congresscally we used a fragment of the putatively ancient ribosomal proteinrotein Degradation targeting undruggables congressS20 (RPS20), which is only structured in the context of the riboso-rotein Degradation targeting undruggables congressmal RNA, to generate a wide-spread fold in living organisms today,rotein Degradation targeting undruggables congressthe TPR fold. After computational optimization of the fragment, werotein Degradation targeting undruggables congressobtained a native-like TPR fold with 2-5 point mutations, which wererotein Degradation targeting undruggables congressneutral in the parent organism, suggesting that they could have beenrotein Degradation targeting undruggables congresssampled in the course of evolution. TPRs could thus have plausiblyrotein Degradation targeting undruggables congressarisen by amplification from an ancestral peptide.