Intrinsic Disorder in Protein Interactions: Insights From a Comprehensive Structural Analysis

Abstract

We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon complex formation and can be localized to binding interfaces. Moreover, analysis of disorder in protein complexes depicts a significant fraction of intrinsically disordered regions, with up to one third of all residues being disordered. We find that the disorder in homodimers, especially in symmetrical homodimers, is significantly higher than in heterodimers and offer an explanation for this interesting phenomenon. We argue that the mechanisms of regulation of binding specificity through disordered regions in complexes can be as common as for unbound monomeric proteins. The fascinating diversity of roles of disordered regions in various biological processes and protein oligomeric forms shown in our study may be a subject of future endeavors in this area.

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

“…Disabling regions prevent any aggregation or association with other partners and might be specific in the sense of preventing the participation in nonspecific functional pathways assisting the functional separation of paralogs. In our previous paper we demonstrated that specific function and binding selectivity in homodimers might be also sustained by disordered loops (52). We should mention, that although here we did not study explicitly the amino acid substitutions which can govern the complex formation, previous studies clearly showed that most of these substitutions involved aromatic and hydrophobic residues which increased binding affinity and stabilized the homooligomer (53,54), but at the same time compromised the specificity and reversibility of the complex formation.…”

RNase Y in Bacillus subtilis: a Natively Disordered Protein That Is the Functional Equivalent of RNase E from Escherichia coli

“…They also allow the evolution of high-specificity, low-affinity interactions where the free energy of the interaction is used for protein folding (14); it is thus likely that RNase Y adopts an ordered structure upon binding to its interaction partners. This disorder-to-order transition is not uncommon in proteins (17). For instance, a C-terminal region of the HPr kinase/phosphorylase adopts an ordered structure only upon binding its target protein, phosphorylated HPr (16).…”

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

“…This subject has been addressed in detail in many recent reviews and other articles. 19,[21][22][23]28,30,32,34,37,38 A classic example is binding of the kinase-inducible transcriptional-activation domain (KID) of cyclic AMP response element-binding protein (CREB) to CREBbinding protein (CBP). Upon binding to CBP, the intrinsically disordered KID polypeptide 39,40 folds with the formation a pair of orthogonal helices.…”