Examples of human PTM-carrying proteins with characteristic PIN-properties and their known disease involvement.

<p>Examples of human PTM-carrying proteins with characteristic PIN-properties and their known disease involvement.</p

The Roles of Post-translational Modifications in the Context of Protein Interaction Networks

<div><p>Among other effects, post-translational modifications (PTMs) have been shown to exert their function via the modulation of protein-protein interactions. For twelve different main PTM-types and associated subtypes and across 9 diverse species, we investigated whether particular PTM-types are associated with proteins with specific and possibly “strategic” placements in the network of all protein interactions by determining informative network-theoretic properties. Proteins undergoing a PTM were observed to engage in more interactions and positioned in more central locations than non-PTM proteins. Among the twelve considered PTM-types, phosphorylated proteins were identified most consistently as being situated in central network locations and with the broadest interaction spectrum to proteins carrying other PTM-types, while glycosylated proteins are preferentially located at the network periphery. For the human interactome, proteins undergoing sumoylation or proteolytic cleavage were found with the most characteristic network properties. PTM-type-specific protein interaction network (PIN) properties can be rationalized with regard to the function of the respective PTM-carrying proteins. For example, glycosylation sites were found enriched in proteins with plasma membrane localizations and transporter or receptor activity, which generally have fewer interacting partners. The involvement in disease processes of human proteins undergoing PTMs was also found associated with characteristic PIN properties. By integrating global protein interaction networks and specific PTMs, our study offers a novel approach to unraveling the role of PTMs in cellular processes.</p></div

Degree, clustering coefficient, closeness centrality analysis for proteins with different PTM-types in each considered species and associated high-confidence STRING and IntAct PIN.

<p>The species are ordered according to their phylogenetic relationships as shown on the left. For every PTM-type, the log-2 of fold difference value for the degree/clustering coefficient/closeness centrality value relative to the respective value associated with proteins not carrying this particular PTM-type are given for PINs based on STRING and IntAct, respectively. Color scale indicates increased (red) or decreased (blue) values in the PTM-set relative to the non-PTM-set with symmetric color intervals (i.e. full color saturation based on the maximal absolute increase or decrease fold difference observed across all values in the table.) Bold-font (underlined) fold-changes indicate significant fold-changes at <i>p</i><0.05 (<i>p</i><0.01) by Mann-Whitney test with FDR correction, the values in red or blue text represent significantly higher or lower network properties, which are inconsistent with the background color based on mean (not median) values. PTM-types “carboxylation”, “proteolytic cleavage”, “hydroxylation”, and “disulfide bond” are not included in this analysis as associated numbers were available for <i>Homo sapiens</i> only.</p

PIN size (number of proteins and interactions) for the nine selected species after excluding the components with the size less than 100.

<p>High confidence PINs extracted from STRING are listed in the “STRING” column, the “IntAct” column contains the PIN sizes extracted from IntAct. The “Common” column indicates the number of common proteins and interactions in STRING and IntAct. Only those proteins with available UniProt ID were considered.</p><p>PIN size (number of proteins and interactions) for the nine selected species after excluding the components with the size less than 100.</p

Protein interaction network properties of proteins associated with different PTM-types in <i>Homo sapiens</i>.

<p>The network property values of proteins annotated to undergo a particular PTM-type or not are shown by violin plots. The number at the top right corner of each graph represents the number of proteins with the corresponding PTM-type and valid network property definitions in <i>Homo sapiens</i>. Protein interactions were taken from the STRING database. The total numbers of proteins and associated number of interactions in <i>Homo sapiens</i> with confidence score>=0.9 were 8,949 and 71,153, respectively. The red (blue) asterisks at the top of violin plot represents the corresponding PTM group has a significantly higher (lower) median value compared to the non-PTM group (*: <i>p</i>-value 0.05, **: <i>p</i>-value 0.01) by Mann-Whitney test with FDR correction. The top 3 PTMs which have high percentage of median difference between PTM group and non-PTM group for each network property are highlighted with red (increased) or blue (decreased) margin.</p

Co-existence network of PTM-types in the proteome of <i>Homo sapiens</i>.

<p>Nodes represent the protein sets associated with the different PTM-types. Edge width was set proportionally to the Jaccard index indicating the overlap between the different protein sets. Edge colors indicate significance with red highlighting PTM-pairs whose overlap was found significant based on Fisher’s exact test with FDR-adjusted <i>p</i>-value threshold set to 0.01, and green otherwise. Numbers in parentheses are the counts of significant “red” co-existence edges to other PTM-types.</p

Heatmap of significant A) biological process and B) GO-Component terms across all studied PTM-types.

<p>The top five GO-terms were included that were found significantly enriched for each PTM-type. Each element in the heat map (Euclidean distance hierarchical clustering, average linkage) represents the grey-scale-encoded <i>p</i>-value, in which a particular combination of PTM-type and GO-term was found significantly enriched. The combined whole UniProtKB-GOA for all the selected species was used as the background set, Fisher’s exact test with FDR correction was used for the enrichment analysis, and the <i>p</i>-value (FDR) threshold indicating significance was set to 0.01.</p

Association of PTM-type and PIN-property specific protein sets with known human disease proteins.

<p>Protein sets were sorted in descending order of the respective PIN-property and the top/bottom 25% tested for overlap with human disease genes reported in OMIM (<a href="http://www.ncbi.nlm.nih.gov/omim" target="_blank">http://www.ncbi.nlm.nih.gov/omim</a>) based on a Fisher’s exact test with FDR-correction with respective counts of proteins binned according to binary decisions top/bottom 25% property and disease association yes/no forming the 2×2 contingency table. <i>p</i>-values highlighted red indicate significant overlap of the top-25% set of proteins for a particular network property with human disease proteins, while blue values signify larger than expected overlaps of the bottom-25% protein sets with proteins annotated to be involved in disease processes at p-value thresholds of <i>p</i>-value 0.05, 0.01 (if underlined), respectively. Black font color indicates no significant overlap of neither the top nor the bottom 25% set.</p><p>Association of PTM-type and PIN-property specific protein sets with known human disease proteins.</p

Frequency table of proteins associated with the selected PTM-types and species.

<p>Listed are the numbers of proteins with the corresponding PTM-type in the respective species.</p><p>Frequency table of proteins associated with the selected PTM-types and species.</p

Significant co-existence pairs of PTM-types across all selected species.

<p>Edge width was set proportionally to the number of species in which a particular PTM pair was found to occur more frequently than expected (see legend to <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004049#pcbi.1004049.g002" target="_blank">Fig. 2</a>) at significance levels of FDR-corrected <i>p</i>-values<0.01. The values on the edges indicate the number of species with significant co-existence normalized by the number of common species between each pair of PTM-types as not all PTM-types are present in all species based on our filtering criteria (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004049#sec004" target="_blank">Methods</a>). Numbers in parentheses are the normalized counts of significant “red” co-existence edges to other PTM-types.</p