Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20352-7. doi: 10.1073/pnas.1012999107. Epub 2010 Nov 3.


The main principles of protein-protein recognition are elucidated by the studies of homooligomers which in turn mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell-cell adhesion processes. Here we explore oligomeric states of homologous proteins in various organisms to better understand the functional roles and evolutionary mechanisms of homooligomerization. We observe a great diversity in mechanisms controlling oligomerization and focus in our study on insertions and deletions in homologous proteins and how they enable or disable complex formation. We show that insertions and deletions which differentiate monomers and dimers have a significant tendency to be located on the interaction interfaces and about a quarter of all proteins studied and forty percent of enzymes have regions which mediate or disrupt the formation of oligomers. We suggest that relatively small insertions or deletions may have a profound effect on complex stability and/or specificity. Indeed removal of complex enabling regions from protein structures in many cases resulted in the complete or partial loss of stability. Moreover, we find that insertions and deletions modulating oligomerization have a lower aggregation propensity and contain a larger fraction of polar, charged residues, glycine and proline compared to conventional interfaces and protein surface. Most likely, these regions may mediate specific interactions, prevent nonspecific dysfunctional aggregation and preclude undesired interactions between close paralogs therefore separating their functional pathways. Last, we show how the presence or absence of insertions and deletions on interfaces might be of practical value in annotating protein oligomeric states.

Publication types

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

MeSH terms

  • Amino Acids / analysis
  • Computational Biology / methods*
  • Databases, Protein
  • Evolution, Molecular*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • INDEL Mutation / genetics*
  • Protein Conformation*
  • Protein Multimerization / genetics
  • Protein Multimerization / physiology*


  • Amino Acids