The Role of Structural Disorder in the Rewiring of Protein Interactions through Evolution

Abstract

Structurally disordered regions play a key role in proteinprotein interaction networks and the evolution of highly connected proteins, enabling the molecular mechanisms for multiple binding. However, the role of protein disorder in the evolution of interaction networks has only been investigated through the analysis of individual proteins, making it impossible to distinguish its specific impact in the (re)shaping of their interaction environments. Now, the availability of large interactomes for several model organisms permits exploration of the role of disorder in protein interaction networks not only at the level of the interacting proteins but of the interactions themselves. By comparing the interactomes of human, fly, and yeast, we discovered that, despite being much more abundant, disordered interactions are significantly less conserved than their ordered counterparts. Furthermore, our analyses provide evidence that this happens not only because disordered proteins are less conserved but also because they display a higher capacity to rewire their interaction neighborhood through evolution. Overall, our results support the hypothesis that conservation of disorder gives a clear evolutionary advantage, facilitating the change of interaction partners during evolution. Moreover, this mechanism is not exclusive of a few anecdotal cases but a global feature present in the interactome networks of entire organisms.

Exon-phase symmetry and intrinsic structural disorder promote modular evolution in the human genome

“…In all, it is rather clear from the examples of overrepresentation that their evolutionary inclusion provides functional advantage, which contributes to fixation of the shuffled exon because it modulates the function of the protein by either affecting activity of the protein or its interactions with partner proteins. This is fully in line with recent observations based on comparing the human, fly and yeast interactomes (36), in which disordered proteins/regions are preferentially involved in rewiring interaction patterns of proteins. In all, all these examples suggest that shuffling enabled by phase symmetry and structural compatibility with the recipient protein because of structural disorder are necessary but not sufficient conditions for the evolution fixation of the shuffled exon: functional compatibility of the novel element of motif/domain must also come into picture for lasting fixation.…”

“…Most of these motifs contribute novel protein–protein interaction sites (partner of SH3 domain and nuclear localization receptor) or post-translational modification site (sumoylation site), i.e. they extend the functionality of the recipient protein in a simple but straightforward way, in accord with recent results showing that disordered regions are often involved in rewiring protein–protein interaction networks (36). That is, their enrichment is a strong indication that their presence provided an adaptive advantage to the gene after shuffling, in accord with our conjecture that not only structural but also functional compatibility with the recipient protein drive the fixation of a shuffled exon.…”

Rapid Evolutionary Dynamics of Structural Disorder as a Potential Driving Force for Biological Divergence in Flaviviruses

“…This supports the hypothesis that phenotypic divergence can result as the conformational flexibility changes, here rewiring protein–protein interaction networks. Further support is provided by a recent study that found interactomes to be depleted in conserved interactions mediated by disordered proteins as compared with ordered proteins networks (Mosca et al 2012). …”

Intrinsic Disorder in PTEN and its Interactome Confers Structural Plasticity and Functional Versatility

“…To confirm our finding of the low mutability of the C-tail region, we also analyzed all human PTEN mutations deposited in the Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/index.php)25 (Figure 2a), cBioPortal for Cancer Genomics2627 (Supplementary Figure S1) and the Roche Cancer Genome Database28 (Supplementary Figure S1) which was consistent with the COSMIC database mutational data. It is likely that evolutionary pressure maintains a survival advantage and ipso facto abrogates progeny with mutations in highly functional protein sequences293031. Thus, the functionally versatile PTEN C-tail IDR cannot afford mutations, hence showing least number of mutations.…”