On the possible amyloid origin of protein folds.

The diversity of protein folds is derived from the diversity of the underlying proteome. Such diversity must have originated from a so-called common ancestor: a hypothetical fold whose identity will, in all likelihood, never be known. Nonetheless, hypotheses exist to explain the evolution of protein folds. When formulating such hypotheses as done here, the entire repertoire of polypeptide structure, from well-defined tertiary structures and molten globule states to intrinsically disordered proteins and oligomeric aggregates, is worth considering. It is the aim of this short essay to discuss the hypothesis that one type of protein aggregate-the cross-β-sheet motif-was the first functional protein fold, that is, the common ancestor fold. Support for this hypothesis comes from the observations that (i) short peptides with simple amino acid sequences are able to form the cross-β-sheet structure, (ii) amyloids can be very stable under harsh conditions, (iii) amyloids can self-assemble in complex mixtures, (iv) amyloids have many potent activities that are attributable to the inherent repetitiveness of the structure, and (v) the proteomes of modern organisms appear to have evolved away from the more amyloidogenic sequences of older organisms, suggesting that amyloids were more ubiquitous earlier in the evolution of modern protein folds.