On the evolution of protein folds: are similar motifs in different protein folds the result of convergence, insertion, or relics of an ancient peptide world?

J Struct Biol. 2001 May-Jun;134(2-3):191-203. doi: 10.1006/jsbi.2001.4393.


This paper presents and discusses evidence suggesting how the diversity of domain folds in existence today might have evolved from peptide ancestors. We apply a structure similarity detection method to detect instances where localized regions of different protein folds contain highly similar sequences and structures. Results of performing an all-on-all comparison of known structures are described and compared with other recently published findings. The numerous instances of local sequence and structure similarities within different protein folds, together with evidence from proteins containing sequence and structure repeats, argues in favor of the evolution of modern single polypeptide domains from ancient short peptide ancestors (antecedent domain segments (ADSs)). In this model, ancient protein structures were formed by self-assembling aggregates of short polypeptides. Subsequently, and perhaps concomitantly with the evolution of higher fidelity DNA replication and repair systems, single polypeptide domains arose from the fusion of ADSs genes. Thus modern protein domains may have a polyphyletic origin.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Amino Acid Motifs / genetics*
  • Amino Acid Sequence / genetics
  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Catalytic Domain / genetics
  • Computational Biology / methods
  • Cytochrome c Group / chemistry
  • Cytochrome c Group / genetics
  • Escherichia coli Proteins*
  • Evolution, Molecular*
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics
  • Humans
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Phosphoprotein Phosphatases / chemistry
  • Phosphoprotein Phosphatases / genetics
  • Phosphotransferases / chemistry
  • Phosphotransferases / genetics
  • Protein Folding*
  • RNA-Binding Proteins*


  • Bacterial Proteins
  • Cytochrome c Group
  • Escherichia coli Proteins
  • Peptides
  • RNA-Binding Proteins
  • era protein, E coli
  • Phosphotransferases
  • Phosphoprotein Phosphatases
  • GTP-Binding Proteins