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 > or = 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.

Figure 1. The Percentages of Hub and End Proteins with ≥30 to ≥100 Consecutive Residues Predicted to Be Disordered

95% confidence intervals were calculated using normal test for two binomial proportions.

Figure 2. The Percentages of Residues Predicted to Be Disordered within Segments of Length ≥ the Value on the x-Axis

Figure 3. Amino Acid Compositions of Hub, End, and Disordered Proteins Are Shown Relative to the Composition of Completely Ordered Globular Proteins

Amino acids are arranged from left to right in order of increasing flexibility as defined by Vihinen et al. [52]. The error bars were calculated as explained in Materials and Methods.

Figure 4. Association of PONDR VL-XT Predicted Disorder with GO Annotations in Yeast

A positive (negative) Z-score indicates that more (less) disorder is associated with the indicated annotation than would be expected by chance. The null distributions for hubs (black bars) and ends (white bars) were generated separately. All associations are significant at a type I, test-wise error rate of 0.05, unless indicated by asterisks. The three branches of GO annotations are plotted separately: (A) biological process, (B) molecular function, and (C) cellular component. o, organization; b, biogenesis.

Figure 5. PONDRing Abp1p and Las17p

(A) The PONDR VL-XT prediction for Abp1p is plotted along with bars representing the positions of the ADF domain (N-terminal orange bar, structure 1HQZ), the SH3 domain (C-terminal orange bar, structure 1JO8), a poly-proline region (green bar), a predicted α-MoRF (blue bar), known phosphorylation sites (black hash marks), and regions critical for Arp2/3 activation (purple bars). (B) The PONDR VL-XT prediction for Las17p is plotted along with bars representing the positions of the WASP homology domain 1 (N-terminal orange bar), WASP homology domain 2 (C-terminal orange bar), poly-proline regions (green bars), and a predicted α-MoRF (blue bar). The number of interaction partners associated with a given region [39] is indicated in the numbered boxes.