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

By Chad Haynes, Christopher J. Oldfield, Fei Ji, Niels Klitgord, Michael E. Cusick, Predrag Radivojac, Vladimir N Uversky, Marc Vidal, Lilia M. Iakoucheva. PLoS Comput. Biol., 2006

576 citations recorded by the source corpus.

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.

Subfields: Aging, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d639760923d43eabeace59f0f42179e0148a06c1

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Citations in the corpus

Intrinsically disordered proteins in human diseases: introducing the D2 concept. (2008, background): “Several of these studies support one of the two primary mechanisms, namely, the common use of disordered regions by hub proteins to bind to multiple partners (33, 45, 65, 102, 122).”
High-throughput prediction of RNA, DNA and protein binding regions mediated by intrinsic disorder (2015, methodology): “This suggests that proteins with more predicted disordered protein-binding regions generally interact with more protein partners, which is consistent with prior results that hub proteins (that interact with at least 10 partners) are enriched in disorder compared to the proteins that interact with on”
Composition Profiler: a tool for discovery and visualization of amino acid composition differences (2007, background): “It has since been used in studies of cell-signalling and cancer-associated proteins [20], serine/arginine-rich splicing factors [21] and hub proteins of PPI networks [18], among others.”
Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. (2011, background): “Essential proteins often occupy critical ‘‘hub’’ positions in the network (Haynes et al., 2006; Jeong et al., 2001).”
Improved Disorder Prediction by Combination of Orthogonal Approaches (2009, background): “This mesh of flavors is accompanied by a variety of functional roles that increase organism complexity [11,19,20,21,22,23,24,25,26].”
MetaDisorder: a meta-server for the prediction of intrinsic disorder in proteins (2012, background): “Intrinsic disorder is a common feature of “ hub ” proteins that interact with multiple other proteins and perform important regulatory roles in the cell [5].”
A decade and a half of protein intrinsic disorder: Biology still waits for physics (2013, background): “Among intriguing protein functions relying on intrinsic disorder are moonlighting activities, 137 actions of hub proteins, 78, 93, 134, [160] [161] [162] [163] [164] and scaffolding functions.”
Intrinsic disorder and functional proteomics. (2007, background): “sapiens) revealed that for all four studied organisms, hub proteins, defined as those that interact with $10 partners, were significantly more disordered than end proteins, defined as those that interact with just one partner (185).”
Natively Unstructured Loops Differ from Other Loops (2007, background): “, may typify a protein–protein interaction hub (a protein with many binding partners in an interaction network) [6,56–59].”
Prediction of Protein Binding Regions in Disordered Proteins (2009, background): “In accordance, several analyses of protein interaction networks revealed that disordered proteins are abundant among hub proteins, proteins with a large number of interacting partners [30,31].”