Conservation of co-evolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone
Protein-protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue co-evolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that co-evolution points to structurally conserved contacts at protein-protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a novel domain-centred protocol to study the interplay between residue co-evolution and structural conservation of protein-protein interfaces. We show that sequence-based co-evolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein-protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence, where standard homology modelling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic co-evolutionary analysis to the prediction of eukaryotic interfaces further illustrates the potential of this novel approach.\n\nSignificance statementInteracting proteins tend to co-evolve through interdependent changes at the interaction interface. This phenomenon leads to patterns of coordinated mutations that can be exploited to systematically predict contacts between interacting proteins in prokaryotes. We explore the hypothesis that co-evolving contacts at protein interfaces are preferentially conserved through long evolutionary periods. We demonstrate that co-evolving residues in prokaryotes identify inter-protein contacts that are particularly well conserved in the corresponding structure of their eukaryotic homologues. Therefore, these contacts have likely been important to maintain protein-protein interactions during evolution. We show that this property can be used to reliably predict interacting residues between eukaryotic proteins with homologues in prokaryotes even if they are very distantly related in sequence.