Bridging Themes: Short Protein Segments Found in Different Architectures

Rachel Kolodny, Sergey Nepomnyachiy, Dan S. Tawfik, Nir Ben-Tal

Research output: Contribution to journalArticlepeer-review


The vast majority of theoretically possible polypeptide chains do not fold, let alone confer function. Hence, protein evolution from preexisting building blocks has clear potential advantages over ab initio emergence from random sequences. In support of this view, sequence similarities between different proteins is generally indicative of common ancestry, and we collectively refer to such homologous sequences as "themes."At the domain level, sequence homology is routinely detected. However, short themes which are segments, or fragments of intact domains, are particularly interesting because they may provide hints about the emergence of domains, as opposed to divergence of preexisting domains, or their mixing-and-matching to form multi-domain proteins. Here we identified 525 representative short themes, comprising 20-80 residues that are unexpectedly shared between domains considered to have emerged independently. Among these "bridging themes"are ones shared between the most ancient domains, for example, Rossmann, P-loop NTPase, TIM-barrel, flavodoxin, and ferredoxin-like. We elaborate on several particularly interesting cases, where the bridging themes mediate ligand binding. Ligand binding may have contributed to the stability and the plasticity of these building blocks, and to their ability to invade preexisting domains or serve as starting points for completely new domains.

Original languageEnglish
Pages (from-to)2191-2208
Number of pages18
JournalMolecular Biology and Evolution
Issue number6
StatePublished - 19 May 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.


  • ancestral segments
  • bridging themes
  • protein evolutionary patterns
  • protein space

ASJC Scopus subject areas

  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology


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