Evidence for the Emergence of β-Trefoils by 'Peptide Budding' from an IgG-like β-Sandwich

Abstract

As sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, {beta}-trefoils have emerged as an uncommon counterexample: They are an isolated protein lineage for which few, if any, sequence or structure associations to other lineages have been identified. If {beta}-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the {beta}-trefoil lineage itself arose de novo. To better understand {beta}-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both {beta}-trefoil bridging themes (evolutionarily-related sequence segments) and {beta}-trefoil-like motifs (structure motifs with a hallmark feature of the {beta}-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering {beta}-trefoil sequence segments or structure motifs rather than the {beta}-trefoil architecture as a whole, as has been done previously. The newly uncovered inter-lineage connections presented here suggest a novel hypothesis about the origins of the {beta}-trefoil fold itself - namely, that it is a derived fold formed by budding from an Immunoglobulin-like {beta}-sandwich protein. These results demonstrate how the emergence of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape natures sewing table.