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Functional Analysis of Human Hub Proteins and Their Interactors Involved in the Intrinsic Disorder-Enriched Interactions

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Functional Analysis of Human Hub Proteins and Their Interactors Involved in the Intrinsic Disorder-Enriched Interactions

Gang Hu et al. Int J Mol Sci.

Abstract

Some of the intrinsically disordered proteins and protein regions are promiscuous interactors that are involved in one-to-many and many-to-one binding. Several studies have analyzed enrichment of intrinsic disorder among the promiscuous hub proteins. We extended these works by providing a detailed functional characterization of the disorder-enriched hub protein-protein interactions (PPIs), including both hubs and their interactors, and by analyzing their enrichment among disease-associated proteins. We focused on the human interactome, given its high degree of completeness and relevance to the analysis of the disease-linked proteins. We quantified and investigated numerous functional and structural characteristics of the disorder-enriched hub PPIs, including protein binding, structural stability, evolutionary conservation, several categories of functional sites, and presence of over twenty types of posttranslational modifications (PTMs). We showed that the disorder-enriched hub PPIs have a significantly enlarged number of disordered protein binding regions and long intrinsically disordered regions. They also include high numbers of targeting, catalytic, and many types of PTM sites. We empirically demonstrated that these hub PPIs are significantly enriched among 11 out of 18 considered classes of human diseases that are associated with at least 100 human proteins. Finally, we also illustrated how over a dozen specific human hubs utilize intrinsic disorder for their promiscuous PPIs.

Keywords: hub proteins; human proteome; intrinsic disorder; intrinsically disordered proteins; protein-protein interactions.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Enrichment in intrinsic disorder of human hub proteins and their interactors. The x- and y-axis show the amount of disorder content of the hubs and hub interactors, respectively. Each protein-protein interaction (PPI) is mapped into this two-dimensional plane and the density of these hub-interactor pairs is represented by green isolines. For instance, 40% of these pairs occupy the lower left corner where the disorder content of both hubs and interactors is below 0.25. The density was modelled with the Epanechnikov kernel function using Mathematica software. Next, we simulated a randomized PPI network that follows the same distribution of node density, i.e., we randomly assigned interactions between the human proteins to maintain the same density profile as in the true PPI network. Coloring of the inside of the two-dimensional plane reflects a relative ratio between the density of true (dn) and randomized (dr) interactions in the PPI networks calculated as [dn(x,y)-dr(x,y)]/dr(x,y). The color scale given on the right defines values of the ratio, e.g., orange corresponds to PPIs which are 0.5 times more frequent in the true PPI network compared to the random network.
Figure 2
Figure 2
Number of disulfide bonds panel (A) and disorder content panel (B) in specific subcellular locations. We report the values for all human proteins (black bars), hubs (solid blue), hub interactors (solid red), and hub interactors that exclude hubs (solid green) that are associated with the disorder-enriched hub PPIs vs the remaining hubs (blue horizontal stripes), hub interactors (red horizontal stripes), and hub interactors that exclude hubs (green horizontal stripes), respectively, for each location. We consider all locations that include at least 10 proteins for each of the seven protein sets. The locations in panel (A,B) are sorted in descending order by the values of the number of disulfide bonds (disorder content) for all proteins (black bars).
Figure 2
Figure 2
Number of disulfide bonds panel (A) and disorder content panel (B) in specific subcellular locations. We report the values for all human proteins (black bars), hubs (solid blue), hub interactors (solid red), and hub interactors that exclude hubs (solid green) that are associated with the disorder-enriched hub PPIs vs the remaining hubs (blue horizontal stripes), hub interactors (red horizontal stripes), and hub interactors that exclude hubs (green horizontal stripes), respectively, for each location. We consider all locations that include at least 10 proteins for each of the seven protein sets. The locations in panel (A,B) are sorted in descending order by the values of the number of disulfide bonds (disorder content) for all proteins (black bars).
Figure 3
Figure 3
Significance of the differences in the functional and structural characteristics between hubs (on the left), all hub interactors, and hub interactors that exclude hubs (on the right) that are associated with the disorder-enriched hub PPIs when compared to the remaining hubs (on the left) and the corresponding remaining interactors (on the right). Panel (A) summarizes the results concerning structural characteristics, functional regions and motifs, evolutionary conservation and the overall abundance of PTMs. Panel (B) gives detailed results for specific types of PTMs. We reported relative differences and their statistical significance. The characteristics are sorted in descending order by their relative differences for the hubs. The characteristics are color-coded as follows: green for large (relative difference > 20%) and statistically significant (p-value < 0.001) enrichment; red for large (relative difference < −20%) and statistically significant (p-value < 0.001) depletion; and blue for lack of large and significant differences (|relative difference| < 20% or p-value over 0.001). Abbreviations: Eukaryotic linear motif (ELM); molecular recognition feature (MoRF; short disordered protein binding region); and posttranslational modification (PTM).
Figure 4
Figure 4
Intrinsic disorder levels in the disordered human hubs characterized by the highest levels of disorder (AE), highly disordered hubs characterized by the highest levels of interactability (FJ), and ordered hubs with the highest interactability levels (KO). The disorder was annotated using the MobiDB platform [141,142,143]; disorder content is shown in red font. Each plot represents disorder tendencies in two forms—by bar plots showing location of IDPRs and by area plots showing sequence distribution of consensus disorder scores evaluated by MobiDB lite disorder predictor [143]. (A) Thyroid hormone receptor-associated protein 3 (UniProt ID: Q9Y2W1). (B) Zinc finger CCCH domain-containing protein 18 (UniProt ID: Q86VM9). (C) Scaffold attachment factor B1 (UniProt ID: Q15424). (D) Intracellular hyaluronan-binding protein 4 (UniProt ID: Q5JVS0). (E) TATA-binding protein-associated factor 2N (UniProt ID: Q92804). (F) BAG family molecular chaperone regulator 3 (UniProt ID: O95817). (G) CREB-binding protein (UniProt ID: Q92793). (H) RNA-binding protein EWS (UniProt ID: Q01844). (I) Cyclin-dependent kinase inhibitor 1 (UniProt ID: P38936). (J) Mediator of DNA damage checkpoint protein 1 (UniProt ID: Q14676). (K) Ubiquitin (UniProt ID: P0CG48; 8548 interactors). (L) Growth factor receptor-bound protein 2 (UniProt ID: P62993; 804 interactors). (M) Actin (UniProt ID: P60709; 263 interactors). (N) Protection of telomeres protein 1 (UniProt ID: Q9NUX5; 200 interactors). (O) Protein mago nashi homolog (UniProt ID: P61326; 190 interactors).
Figure 5
Figure 5
Structural characterization of highly connected ordered hubs. (A) Solution NMR structure of human ubiquitin (PDB ID: 1XQQ) [207]. (B) Solution NMR structure of a complex between the N-terminal SH3 domain of GRB2 (residues 1–56, red ribbons) and a peptide from SOS (blue ribbons) (PDB ID: 1AZE) [210]. (C) Minimized mean solution NMR structure of a complex between the SH2 domain of human GRB2 (residues 49–168, red ribbon) and a KPFY*VNVEF peptide (blue ribbon) (PDB ID: 1BMB) [211]. (D) Minimized mean solution NMR structure of a complex between the C-terminal SH3 domain of human GRB2 (residues 159–215, red ribbon) and a ligand peptide (blue ribbon) (PDB ID: 1IO6). (E) Crystal structure of a telomeric shelterin complex between the POT1 C-terminal domain (POT1C, residues 330–634, red ribbon) and POT1-binding region (residues 254–336, blue ribbon) of the adrenocortical dysplasia protein homolog (PDB ID: 5JUN7) [212]. (F) Crystal structure of a core EJC complex containing the complex of MAGOH (full length, dark orange ribbon), Y14 (residues 66–174, light orange ribbon), eIF4AIII (full length, red ribbon), Btz (the SELOR domain, residues 137–286, two blue ribbons), a non-hydrolyzable ATP analog (AMPPNP, bound to eIF4AIII), and U15 RNA (yellow ribbon) (PDB ID: 2J0Q) [213].
Figure 6
Figure 6
Connectivity of proteins in the human PPI network. Panel (A) summarizes the fraction of proteins (nodes in the PPI network) with a given number of PPI interactions (degree). Panel (B) gives the cumulative fraction of proteins having a degree less than the corresponding value on the x-axis. The circles (crosses) show the results for the original PPI network collected from mentha (the network where proteins were mapped to UniProt). The dashed vertical line in panel (B) shows the degree that demarcates hubs, which is defined as the 20% of the most connected nodes.

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