Evidence for the emergence of β-trefoils by 'Peptide Budding' from an IgG-like β-sandwich

Author summaryJudged by sequence and structure, about 2,500 different protein evolutionary lineages have been identified to date. Since proteins are central to life, understanding where they came from and how they continue to change is a key challenge in biology. We probed the origins of a relatively recent protein lineage, the beta-trefoil, looking at patterns of sequence or structure that are shared between beta-trefoils and other protein lineages. On the basis of these shared patterns, we argue that a peptide fragment from the ancient IgG-like beta-sandwich evolutionary lineage gave rise to beta-trefoils via a process we call peptide budding. Revealing and understanding cryptic associations between seemingly distinct protein families can shed light on the mechanisms by which new proteins emerge, and contributes to the growing appreciation that the protein universe is highly connected. 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 evolution of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape nature's sewing table.

Automated summary

This study reveals the origin of the beta-trefoil protein lineage and suggests that it arose from a peptide fragment of the ancient IgG-like beta-sandwich lineage through a process called peptide budding. The findings highlight the interconnectedness of the protein universe and the evolutionary mechanisms by which new proteins emerge.