Is the intrinsic disorder of proteins the cause of the scale‐free architecture of protein–protein interaction networks?

Schnell, Santiago; Fortunato, Santo; Roy, Sourav

doi:10.1002/pmic.200600455

Cited by 22 publications

(21 citation statements)

References 35 publications

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“…However, it should be noted that many ordered proteins also have many binding partners, via the same binding site or separate binding sites on the protein surface [16, 17]. Some studies have suggested a correlation between the increase in the number of interaction partners and the increase in the propensity of disorder [18, 19], but this conclusion has been debated [17, 20]. …”

Section: Binding Promiscuitymentioning

confidence: 99%

Intrinsic disorder: signaling via highly specific but short-lived association

Zhou

2012

Trends in Biochemical Sciences

124

159

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The association between signaling proteins and their cellular targets is generally thought to be highly specific (implicating a high association constant, Ka) and, at the same time, transient or short-lived (corresponding to a high dissociation rate constant, kd). However, a combination of high Ka and high kd would lead to a high association rate constant (ka = Kakd), which poses a problem because there is a limit to which ka can be increased, set by the diffusional approach to form the complex. In this Opinion, I propose that having the signaling protein disordered before binding the target provides a way out of this quandary. The intrinsic disorder of the signaling protein would decrease Ka without sacrificing the specificity of the complex, and thereby would allow kd to be increased to a range appropriate for signaling.

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Section: Binding Promiscuitymentioning

confidence: 99%

Intrinsic disorder: signaling via highly specific but short-lived association

Zhou

2012

Trends in Biochemical Sciences

124

159

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“…A controversial debate has been focused on the occurrence and the role of structural disorder in hub functionality (Ekman et al, 2006; Schnell et al, 2007; Singh et al, 2007; Kim et al, 2008). From completely unstructured polypeptides to compact, molten globule-like ensembles containing substantial secondary structure, a variety of intrinsically disordered proteins (IDPs) has been already isolated (Marsh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

et al. 2014

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Cell growth and proliferation require a complex series of tight-regulated and well-orchestrated events. Accordingly, proteins governing such events are evolutionary conserved, even among distant organisms. By contrast, it is more singular the case of “core functions” exerted by functional analogous proteins that are not homologous and do not share any kind of structural similarity. This is the case of proteins regulating the G1/S transition in higher eukaryotes–i.e., the retinoblastoma (Rb) tumor suppressor Rb—and budding yeast, i.e., Whi5. The interaction landscape of Rb and Whi5 is quite large, with more than one hundred proteins interacting either genetically or physically with each protein. The Whi5 interactome has been used to construct a concept map of Whi5 function and regulation. Comparison of physical and genetic interactors of Rb and Whi5 allows highlighting a significant core of conserved, common functionalities associated with the interactors indicating that structure and function of the network—rather than individual proteins—are conserved during evolution. A combined bioinformatics and biochemical approach has shown that the whole Whi5 protein is highly disordered, except for a small region containing the protein family signature. The comparison with Whi5 homologs from Saccharomycetales has prompted the hypothesis of a modular organization of structural disorder, with most evolutionary conserved regions alternating with highly variable ones. The finding of a consensus sequence points to the conservation of a specific phosphorylation rhythm along with two disordered sequence motifs, probably acting as phosphorylation-dependent seeds in Whi5 folding/unfolding. Thus, the widely disordered Whi5 appears to act as a hierarchical, “date hub” that has evolutionary assayed an original way of modular organization before being supplanted by the globular, multi-domain structured Rb, more suitable to cover the role of a “party hub”.

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“…degree distribution and clustering coefficient) in a mutually exclusive manner, to understand the local properties of a node. [19][20][21] Consequently, questions have been raised on the generality of the trends. 15 Also of relevance in this context is the link between the structure and dynamics of a network which is most often neglected when studying global properties.…”

Section: Introductionmentioning

confidence: 99%

Extensive cross-talk and global regulators identified from an analysis of the integrated transcriptional and signaling network in Escherichia coli

2012

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To understand the regulatory dynamics of transcription factors (TFs) and their interplay with other cellular components we have integrated transcriptional, protein-protein and the allosteric or equivalent interactions which mediate the physiological activity of TFs in Escherichia coli. To study this integrated network we computed a set of network measurements followed by principal component analysis (PCA), investigated the correlations between network structure and dynamics, and carried out a procedure for motif detection. In particular, we show that outliers identified in the integrated network based on their network properties correspond to previously characterized global transcriptional regulators. Furthermore, outliers are highly and widely expressed across conditions, thus supporting their global nature in controlling many genes in the cell. Motifs revealed that TFs not only interact physically with each other but also obtain feedback from signals delivered by signaling proteins supporting the extensive cross-talk between different types of networks. Our analysis can lead to the development of a general framework for detecting and understanding global regulatory factors in regulatory networks and reinforces the importance of integrating multiple types of interactions in underpinning the interrelationships between them.

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Is the intrinsic disorder of proteins the cause of the scale‐free architecture of protein–protein interaction networks?

Cited by 22 publications

References 35 publications

Intrinsic disorder: signaling via highly specific but short-lived association

Intrinsic disorder: signaling via highly specific but short-lived association

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

Extensive cross-talk and global regulators identified from an analysis of the integrated transcriptional and signaling network in Escherichia coli

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