Abstract
Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction networks, due to the lack of strict structural constraints, they undergo faster evolutionary changes than folded domains. This makes the reliable identification and alignment of IDP homologs difficult, which led to IDPs being omitted in most large-scale residue co-variation analyses. By preforming a dedicated analysis of phylogenetically widespread bacterial IDP–partner interactions, here we demonstrate that partner binding imposes constraints on IDP sequences that manifest in detectable interprotein ECs. These ECs were not detected for interactions mediated by short motifs, rather for those with larger IDP–partner interfaces. Most identified coupled residue pairs reside close (<10 Å) to each other on the interface, with a third of them forming multiple direct atomic contacts. EC-carrying interfaces of IDPs are enriched in negatively charged residues, and the EC residues of both IDPs and partners preferentially reside in helices. Our analysis brings hope that IDP–partner interactions difficult to study could soon be successfully dissected through residue co-variation analysis.
Highlights
Protein sequences provide rich information on structural and functional constraints in the form of residue co-variation in evolution
Even though bacterial proteomes are relatively poor in intrinsically disordered proteins (IDPs)/IDRs [42,43,44], we restricted our search to bacterial IDP–partner interactions to ensure a sufficient number and diversity of orthologous sequences for residue co-variation analysis
We analyzed the 42 bacterial IDPs bound to their folded partners available in the Database of disordered binding sites (DIBS) [45] because there the structural states of the constituent protein chains are backed by experimental evidence
Summary
Protein sequences provide rich information on structural and functional constraints in the form of residue co-variation in evolution. Several groups have demonstrated that the analysis of sequence co-variation can be efficiently used for predicting protein structures [2,3,4,5,6,7,8,9,10], including transmembrane proteins [11,12], defining evolutionary units within proteins [13], and identifying contacting residues of interaction partners [14,15], and interacting subunits of larger complexes [14]. The conformational variability and adaptability, extended interaction surface, various embedded interaction motifs [21,22], and post-translational modification sites [23] of IDPs make structural disorder indispensable in regulatory [24], complex-assembly [25], and scaffolding [26,27] functions. IDPs are central to cellular interaction networks [28,29] and are frequently associated with human diseases [30]
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