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

PLoS Comput Biol. 2022 Feb 14;18(2):e1009833. doi: 10.1371/journal.pcbi.1009833. eCollection 2022 Feb.

Abstract

As sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, β-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 β-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the β-trefoil lineage itself arose de novo. To better understand β-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both 'β-trefoil bridging themes' (evolutionarily-related sequence segments) and 'β-trefoil-like motifs' (structure motifs with a hallmark feature of the β-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering β-trefoil sequence segments or structure motifs rather than the β-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 β-trefoil fold itself-namely, that it is a derived fold formed by 'budding' from an Immunoglobulin-like β-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Immunoglobulin G
  • Models, Molecular
  • Peptides* / chemistry
  • Protein Folding
  • Trefoil Factors* / chemistry

Substances

  • Immunoglobulin G
  • Peptides
  • Trefoil Factors

Grants and funding

This material is based upon work supported by the National Science Foundation (award #1724300 to S.E.M.) and the VW Foundation (grant #94747 to R.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.