A recent in silico analysis indicated that relatively small insertions and deletions in protein interfaces can differentiate between monomers and homodimers, and that these elements may preclude undesired interactions ( 6). Understanding the principles of protein–protein interactions in general, and the assurance of interaction specificity despite the limited number of interface geometries in particular, is an important biological challenge. In sum, our complementary in silico, in vitro, and in vivo analysis argues that interface add-ons are a practical and widespread evolutionary strategy to prevent the formation of nonphysiological complexes by specializing protein–protein interactions. Moreover, growth experiments showed that the lack of interface add-ons can lead to physiologically harmful cross-talk between essential biosynthetic pathways. The importance of interface add-ons for protein–protein interaction specificity is demonstrated by an exemplary experimental characterization of over 30 cognate and hybrid glutamine amidotransferase complexes in combination with comprehensive genetic profiling and protein design. We identified interface add-ons in 10% of a representative set of bacterial, heteromeric protein complexes. Here, we describe structural elements called interface add-ons that fulfill this function and elucidate their role for the diversification of protein–protein interactions during evolution. This raises the question of how protein–protein interaction specificity is achieved on the structural level and how the formation of nonphysiological complexes is avoided. However, the number of different protein folds and interface geometries found in nature is limited. Cells contain a multitude of protein complexes whose subunits interact with high specificity.
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