Protein coadaptation and the design of novel approaches to identify protein–protein interactions

Abstract

SummaryProteins rarely function in isolation but they form part of complex networks of interactions with other proteins within or among cells. The importance of a particular protein for cell viability is directly dependent upon the number of interactions where it participates and the function it performs: the larger the number of interactions of a protein the greater its functional importance is for the cell. With the advent of genome sequencing and ''omics'' technologies it became feasible conducting large-scale searches for protein interacting partners. Unfortunately, the accuracy of such analyses has been underwhelming owing to methodological limitations and to the inherent complexity of protein interactions. In addition to these experimental approaches, many computational methods have been developed to identify protein-protein interactions by assuming that interacting proteins coevolve resulting from the coadaptation dynamics between the amino acids of their interacting faces. We review the main technological advances made in the field of interactomics and discuss the feasibility of computational methods to identify protein-protein interactions based on the estimation of coevolution. As proof-of-concept, we present a classical case study: the interactions of cell surface proteins (receptors) and their ligands. Finally, we take this discussion one step forward to include interactions between organisms and species to understand the generation of biological complexity. Development of technologies for accurate detection of proteinprotein interactions may shed light on processes that go from the fine-tuning of pathways and metabolic networks to the emergence of biological complexity.

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…This approach is distinct from the concept of structural compensation or coadaptation, for which mutations on one partner are linked to compensating mutations on the partner. 76 It would certainly be possible to lift the requirement of MoRF sequence identity to thereby study coadaptation in complexes involving disordered proteins. Indeed, we have work in progress along these lines for a few specific examples to determine whether coadaptation between two structured proteins is different from coadaptation between structured proteins and MoRFs.…”

Intrinsic Protein Disorder and Protein-Protein Interactions

“…We immediately tried to suggest that the new principle was likely the use of disordered proteins by means of coupled binding and folding, which had been previously suggested for protein-DNA interactions [25] as well as for one protein binding to several partners [26], but publication of these ideas for hub proteins was delayed somewhat [3]. By now there is strong evidence that, at least for many if not all hub-partner interactions, disorder plays an important role in enabling one protein to bind to multiple partners [3][4][5][6].…”

“…In general, the mutations on one partner are frequently linked to mutations on the other partner, indicating structural compensation or coadaptation across the binding interface [26]. However, the interacting protein pairs we collected here are a special set in that only the partners show amino acid substitutions in their sequences, whereas the MoRFs' sequences are unchanged.…”

Coevolution analyses illuminate the dependencies between amino acid sites in the chaperonin system GroES-L

“…The performance of alternative functions is dependent on the fixation of mutations in genes. Since amino acids are constrained by their interactions with other amino acids, fixation of mutations at sites with functional relevance must be accompanied by mutations in other sites of the protein through molecular coadaptation dynamics—that is, amino acids that are structurally or functionally linked exercise reciprocal natural selection on one another [59]. …”