Intrinsic Disorder Is a Common Feature of Hub Proteins from Four Eukaryotic Interactomes

Abstract

Recent proteome-wide screening approaches have provided a wealth of information about interacting proteins in various organisms. To test for a potential association between protein connectivity and the amount of predicted structural disorder, the disorder propensities of proteins with various numbers of interacting partners from four eukaryotic organisms (Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens) were investigated. The results of PONDR VL-XT disorder analysis show that for all four studied organisms, hub proteins, defined here as those that interact with ≥10 partners, are significantly more disordered than end proteins, defined here as those that interact with just one partner. The proportion of predicted disordered residues, the average disorder score, and the number of predicted disordered regions of various lengths were higher overall in hubs than in ends. A binary classification of hubs and ends into ordered and disordered subclasses using the consensus prediction method showed a significant enrichment of wholly disordered proteins and a significant depletion of wholly ordered proteins in hubs relative to ends in worm, fly, and human. The functional annotation of yeast hubs and ends using GO categories and the correlation of these annotations with disorder predictions demonstrate that proteins with regulation, transcription, and development annotations are enriched in disorder, whereas proteins with catalytic activity, transport, and membrane localization annotations are depleted in disorder. The results of this study demonstrate that intrinsic structural disorder is a distinctive and common characteristic of eukaryotic hub proteins, and that disorder may serve as a determinant of protein interactivity. From the formulation of Emil Fisher's lock-and-key hypothesis in 1894 until the early 1990s, a dominating and widely accepted concept in molecular biology was the protein structure–function paradigm. According to this concept, a protein can perform its biological function(s) only after folding into a specific rigid 3-D structure. Only recently has the validity of this structure–function paradigm been seriously challenged, primarily through the wealth of counterexamples that have gradually accumulated over the past 15 years. These counterexamples demonstrated that many proteins exist in a natively unfolded (or intrinsically disordered) state, and function without a prerequisite stably folded structure. In many cases, the lack of structure is required for biological function. Previous results have implicated intrinsic disorder as having an important role in protein interactions. The authors generalize this notion by comparing interaction networks from four eukaryotic organisms: yeast, worm, fly, and human. They have found that within these networks the proteins that interact with multiple protein partners (network hubs) are significantly more disordered than proteins that interact with a single protein partner (network ends). The results of this study demonstrate that intrinsic structural disorder is a distinctive and common characteristic of hub proteins, and that disorder may serve as a determinant of protein interactivity.