Bioinformatic Analysis of the Role of Intrinsic Disorder in Multiple Specificity

Abstract

Several lines of evidence suggest that intrinsically disordered proteins (IDPs) are a common mechanism used by nature to mediate protein-protein interactions. IDPs lack a stable three-dimensional structure under physiological conditions and many such proteins have been characterized by several biophysical methods. Additionally, IDPs are estimated to be abundant within various proteomes, particularly eukaryotes, and carry out a variety of molecular functions without the prerequisite of a specific, stable structure. It is thought that IDPs can facilitate protein interactions through an ability to mediate binding diversity, where one of the proposed mechanisms for this is multiple specificity - i.e. recognition of multiple molecular partners through use of the same binding residues - through contextual folding of IDPs.In previous work, two contrasting examples of proteins with multiple binding specificity were examined, 14-3-3ζ and p53, which exemplify the potential of intrinsic disorder for mediating protein interactions. 14-3-3ζ has a structured domain with a single binging pocket that is responsible for the binding of various protein partners through interaction with sequence divergent intrinsically disordered segments in these partners. In contrast, the disordered termini of p53 contain discrete regions that are each involved in many interactions with different protein partners, where these interactions carry out and regulate p53 function. The common theme in both of these examples is structural variability in the bound state that is enabled by intrinsic disorder in one of the partners in the unbound state.In current work, the previous analysis is expanded to many other examples of proteins that interact with multiple partners using a common binding site. These data support the conjecture that intrinsic disorder enables binding to multiple partners and provides detailed information about induced fit in structured regions.