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.
Highlights
Systematic binary protein–protein interaction maps with various percentages of proteome coverage are currently available for S. cerevisiae [1,2], C. elegans [3], D. melanogaster [4], H. pylori [5], and, most recently, for H. sapiens [6,7]
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
The investigation of the disorder content of proteins from four eukaryotic interactomes shows that hub proteins are more disordered than end proteins in all four studied organisms (Figures 1 and 2), even though the predicted disorder content differs among these organisms [11,12]
Summary
Systematic binary protein–protein interaction maps with various percentages of proteome coverage are currently available for S. cerevisiae [1,2], C. elegans [3], D. melanogaster [4], H. pylori [5], and, most recently, for H. sapiens [6,7]. While much has been learned to date about the general mechanisms of protein–protein interactions, the specific structural features that account for differences in protein interactivity are still unknown. It has recently been suggested that intrinsically disordered (ID) proteins play an important role in protein–protein interactions [9,10]. The lack of prior structure provides several advantages to ID-mediated protein interactions relative to interactions between folded proteins, such as decoupling of specificity and affinity, and the ability to Editor: Cheryl Arrowsmith, University of Toronto, Canada
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