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. , and, most recently, for H. sapiens [6,7]. As a result of these studies, it is now proposed that most networks within the cell have similar overall broad-scale topology where most proteins interact with just a few partners and a small number of proteins interact with many partners. Although all currently available networks represent only samples of the complete interactomes [8], the investigation of such partial networks is a first step toward a systems-biology understanding of cells and organisms.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]. ID proteins and protein regions lack a unique 3-D structure and exist in a dynamic ensemble of conformations. More than 427 proteins containing 802 disordered regions have been annotated (http://www.disprot.org). Computational estimates suggest that eukaryotic proteomes have a significantly higher occurrence of ID proteins relative to prokaryotic proteomes [11,12]. The prevalence of ID proteins in eukaryotes is likely to be due t...

The human RBPome: From genes and proteins to human disease

“…Intrinsically disordered proteins are known to be highly interacting due to their unstable 3D structure and hence form hubs in their protein-protein interaction networks [44,46,47]. This property of disordered proteins being hubs in their protein-protein interaction network has been analysed in our current study.…”

“…RBPs being diverse structurally and functionally, are known to be highly disordered [43,44]. Intrinsic structural disorder of the RBPs was predicted using IUPRED, which predicts disorder on a per-residue basis [22,23] (Materials and Methods).…”

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…We further suggested two ways that disorder could be used by hub proteins for binding to multiple partners: (1) One region of disorder could bind to many different partners (one-to-many binding), so the hub protein itself uses disorder for multiple partner binding; and (2) many different regions of disorder could bind to a single partner (many-to-one binding), so the hub protein is structured but binds to many disordered partners via interaction with disorder. 8 Since this initial proposal, we [9][10][11] and many others [12][13][14][15][16][17][18][19][20][21][22] have provided additional evidence that hubs and/or their binding partners are especially enriched in intrinsic disorder, with both the many-to-one and one-to-many processes involving the use of intrinsic disorder.…”

CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices

“…Prediction of intrinsically disordered proteins in complete genomes shows an increasing proportion of disordered proteins with increasing organism complexity: up to 14% of archaeal, 21% of bacterial and 41% of eukaryotic proteins are predicted to contain stretches of more than 50 disordered residues 18 . Key regulatory cell-signaling proteins and human cancer-associated proteins show greater amounts of intrinsic disorder than proteins involved in metabolism, biosynthesis or degradation 19 , and proteins classified as hub proteins (more than ten interaction partners) are enriched in disordered regions compared with end proteins (only one interaction partner) 20 . The intrinsic plasticity of disordered proteins may facilitate their regulated binding to a variety of binding partners 16 .…”