Complex evolutionary footprints revealed in an analysis of reused protein segments of diverse lengths

Sergey Nepomnyachiy, Nir Ben-Tal, Rachel Kolodny

Research output: Contribution to journalArticlepeer-review


Proteins share similar segments with one another. Such “reused parts”—which have been successfully incorporated into other proteins—are likely to offer an evolutionary advantage over de novo evolved segments, as most of the latter will not even have the capacity to fold. To systematically explore the evolutionary traces of segment “reuse” across proteins, we developed an automated methodology that identifies reused segments from protein alignments. We search for “themes”—segments of at least 35 residues of similar sequence and structure—reused within representative sets of 15,016 domains [Evolutionary Classification of Protein Domains (ECOD) database] or 20,398 chains [Protein Data Bank (PDB)]. We observe that theme reuse is highly prevalent and that reuse is more extensive when the length threshold for identifying a theme is lower. Structural domains, the best characterized form of reuse in proteins, are just one of many complex and intertwined evolutionary traces. Others include long themes shared among a few proteins, which encompass and overlap with shorter themes that recur in numerous proteins. The observed complexity is consistent with evolution by duplication and divergence, and some of the themes might include descendants of ancestral segments. The observed recursive footprints, where the same amino acid can simultaneously participate in several intertwined themes, could be a useful concept for protein design. Data are available at

Original languageEnglish
Pages (from-to)11703-11708
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - 31 Oct 2017

Bibliographical note

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.


  • Ancestral segments
  • Protein evolutionary patterns
  • Protein function annotation
  • Protein space

ASJC Scopus subject areas

  • General


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