Presented at ISMB2017

Altmetric score 16.15 (top 6%)

Author: Juan Rodriguez-Rivas
Research area: bioinformatics

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Conservation of co-evolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone

Created on 3rd August 2016

Juan Rodriguez-Rivas; Simone Marsili; David Juan; Alfonso Valencia;

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 (the twilight zone), where standard homology modelling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residues 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.

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