Intra-chain 3D segment swapping spawns the evolution of new multidomain protein architectures

J Mol Biol. 2012 Jan 6;415(1):221-35. doi: 10.1016/j.jmb.2011.10.045. Epub 2011 Nov 4.


Multidomain proteins form in evolution through the concatenation of domains, but structural domains may comprise multiple segments of the chain. In this work, we demonstrate that new multidomain architectures can evolve by an apparent three-dimensional swap of segments between structurally similar domains within a single-chain monomer. By a comprehensive structural search of the current Protein Data Bank (PDB), we identified 32 well-defined segment-swapped proteins (SSPs) belonging to 18 structural families. Nearly 13% of all multidomain proteins in the PDB may have a segment-swapped evolutionary precursor as estimated by more permissive searching criteria. The formation of SSPs can be explained by two principal evolutionary mechanisms: (i) domain swapping and fusion (DSF) and (ii) circular permutation (CP). By large-scale comparative analyses using structural alignment and hidden Markov model methods, it was found that the majority of SSPs have evolved via the DSF mechanism, and a much smaller fraction, via CP. Functional analyses further revealed that segment swapping, which results in two linkers connecting the domains, may impart directed flexibility to multidomain proteins and contributes to the development of new functions. Thus, inter-domain segment swapping represents a novel general mechanism by which new protein folds and multidomain architectures arise in evolution, and SSPs have structural and functional properties that make them worth defining as a separate group.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Databases, Protein
  • Evolution, Molecular*
  • Imaging, Three-Dimensional / methods
  • Models, Molecular
  • Protein Folding
  • Protein Structure, Tertiary
  • Proteome / chemistry*
  • Proteome / genetics*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structural Homology, Protein


  • Proteome