Abstract
Posttranslational regulation of protein function is an ubiquitous mechanism in eukaryotic cells. Here, we analyzed biological properties of nodes and edges of a human protein-protein interaction phosphorylation-based network, especially of those nodes critical for the network controllability. We found that the minimal number of critical nodes needed to control the whole network is 29%, which is considerably lower compared to other real networks. These critical nodes are more regulated by posttranslational modifications and contain more binding domains to these modifications than other kinds of nodes in the network, suggesting an intra-group fast regulation. Also, when we analyzed the edges characteristics that connect critical and non-critical nodes, we found that the former are enriched in domain-to-eukaryotic linear motif interactions, whereas the later are enriched in domain-domain interactions. Our findings suggest a possible structure for protein-protein interaction networks with a densely interconnected and self-regulated central core, composed of critical nodes with a high participation in the controllability of the full network, and less regulated peripheral nodes. Our study offers a deeper understanding of complex network control and bridges the controllability theorems for complex networks and biological protein-protein interaction phosphorylation-based networked systems.
Highlights
Fold completely, remaining flexible[8]
Whereas domain-domain interactions (DDIs) tend to be characterized by large, strong interfaces between two globular domains, domains-linear motif interactions (DLIs) are typically composed of small, weak interfaces between a domain and a short peptide
eukaryotic linear motifs (ELMs) are very important in the evolution and rewiring of PPINs10, because of they are often located within intrinsically disordered regions (IDRs) of proteins[11,12]
Summary
Fold completely, remaining flexible[8]. The main difference relay on the fact that IDRs generally contain eukaryotic linear motifs (ELMs) within the disordered region component. Eukaryotic proteomes include a large fraction (~30%) of long regions that are natively disordered, and do not adopt a fixed structure[14] These regions have key physiological roles; for example, they are involved as communicators in many cellular signaling pathways[15]. The 14-3-3 protein family members interact with phosphorylated partners (phospho-serine or threonine) in a way that they act as “readers” of this widespread PTM in signaling cascades[19]. They interact with their partners through the recognition of phosphorylated linear motifs located within disordered regions[19,20]. We simulated a progressive elimination of one 14-3-3 isoform at a time to assess how the network is affected, trying to emulate for example the inhibition of 14-3-3ζisoform by the acetylation of its critical residue Lys[49]
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