The modular architecture of protein-protein binding interfaces

D. Reichmann, O. Rahat, S. Albeck, R. Meged, O. Dym, G. Schreiber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

220 Scopus citations


Protein-protein interactions are essential for life. Yet, our understanding of the general principles governing binding is not complete. In the present study, we show that the interface between proteins is built in a modular fashion; each module is comprised of a number of closely interacting residues, with few interactions between the modules. The boundaries between modules are defined by clustering the contact map of the interface. We show that mutations in one module do not affect residues located in a neighboring module. As a result, the structural and energetic consequences of the deletion of entire modules are surprisingly small. To the contrary, within their module, mutations cause complex energetic and structural consequences. Experimentally, this phenomenon is shown on the interaction between TEM1-β-lactamase and β-lactamase inhibitor protein (BLIP) by using multiple-mutant analysis and x-ray crystallography. Replacing an entire module of five interface residues with Ala created a large cavity in the interface, with no effect on the detailed structure of the remaining interface. The modular architecture of binding sites, which resembles human engineering design, greatly simplifies the design of new protein interactions and provides a feasible view of how these interactions evolved.

Original languageAmerican English
Pages (from-to)57-62
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - 4 Jan 2005
Externally publishedYes


  • Binding energy
  • Cluster analysis
  • Protein-protein interaction
  • Structure


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