Dynamic interactions of proteins in complex networks: a more structured view

Stein, Amelie; Pache, Roland A.; Bernadó, Pau; Pons, Miquel; Aloy, Patrick

doi:10.1111/j.1742-4658.2009.07251.x

Cited by 105 publications

(97 citation statements)

References 118 publications

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“…Long disordered segments are a common feature observed in a large percentage of proteins; being prevalent especially among proteins involved in vital processes, such as transcription, translation, signal transduction, and protein phosphorylation (47,145). Such unstructured regions may provide versatility in recognizing multiple targets, promoting communication with many proteins in response to environmental changes; thus, expanding the capacities of ordered complexes and representing a powerful strategy selected by nature to quickly explore a vast interaction space with unique thermodynamic advantages (132). Disordered regions were shown to be prevalent in DNA binding proteins, particularly in those involved in targeted sequence binding (e.g., repair proteins and transcription factors) (143,153).…”

Section: Relevance Of the Unfolded Domains In Ber Proteinsmentioning

confidence: 99%

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

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Section: Relevance Of the Unfolded Domains In Ber Proteinsmentioning

confidence: 99%

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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“…In systems other than transcription, interactions between disordered peptides and structured proteins often are mediated although short linear motifs (SLMs) (39)(40)(41)(42). These short motifs, ∼3-10 residues in length, are found in otherwise unrelated proteins where they mediate molecular interactions, e.g., peptide motifs mediating specific binding to the SH2, SH3, and 14-3-3 domains, as well as motifs such as kinase, acetylase, or methylase recognition sites.…”

mentioning

confidence: 99%

A sequence-specific transcription activator motif and powerful synthetic variants that bind Mediator using a fuzzy protein interface

Warfield

Tuttle

Pacheco

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

173

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Although many transcription activators contact the same set of coactivator complexes, the mechanism and specificity of these interactions have been unclear. For example, do intrinsically disordered transcription activation domains (ADs) use sequence-specific motifs, or do ADs of seemingly different sequence have common properties that encode activation function? We find that the central activation domain (cAD) of the yeast activator Gcn4 functions through a short, conserved sequence-specific motif. Optimizing the residues surrounding this short motif by inserting additional hydrophobic residues creates very powerful ADs that bind the Mediator subunit Gal11/Med15 with high affinity via a "fuzzy" protein interface. In contrast to Gcn4, the activity of these synthetic ADs is not strongly dependent on any one residue of the AD, and this redundancy is similar to that of some natural ADs in which few if any sequence-specific residues have been identified. The additional hydrophobic residues in the synthetic ADs likely allow multiple faces of the AD helix to interact with the Gal11 activator-binding domain, effectively forming a fuzzier interface than that of the wild-type cAD.Mediator complex | protein NMR T ranscription activators are regulators of cell identity, cell growth, and the response to environmental conditions. These highly regulated factors contain one or more activation domains (ADs) that typically bind coactivators-the complexes that contact the transcription machinery and/or have chromatin modifying activity (1-5). AD-coactivator binding initiates a cascade of events leading to productive transcription including targeted chromatin remodeling and stimulation of both RNA polymerase II preinitiation complex formation and transcription elongation (6). Many broadly acting ADs bind several coactivators, allowing them to function at a wide range of promoters with different coactivator requirements (7)(8)(9)(10)(11)(12)(13)(14). The function of most tested ADs is conserved among eukaryotes (15, 16), even though some key activator targets are not conserved. For example, the herpes virus protein VP16 strongly activates transcription in both yeast and mammalian cells, although human Med25, a critical target of VP16 in humans, is not found in yeast (17,18). Thus, the ability to adapt to different coactivator targets is seemingly a key property of ADs.Defining what constitutes a functional AD has been difficult, because there is little apparent sequence similarity among different ADs. All structurally characterized eukaryotic ADs lack a stable 3D structure and are disordered in the absence of a coactivator target (19)(20)(21)(22)(23)(24)(25). Initial studies classified ADs based on enriched residues: acidic proline-, glutamine-, or serine-rich activators (26). However, these residue types later were found to be generally enriched in intrinsically disordered proteins and were termed "disorder-promoting residues" (27, 28).Attempts to define functional sequence motifs within ADs have led to ambiguous results. For many ...

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“…This, however, also serves as a potential point of attack for many successful viruses (such as HIV or ebola) that also harbor disordered proteins containing various motifs [84]. Apart from individual examples, the connection between protein disorder and motif regulation has been also shown at a more general level [87].…”

Section: Linear Motifs and Disordered Binding Regionsmentioning

confidence: 99%

Bioinformatical Approaches to Unstructured/Disordered Proteins and Their Interactions

Mészáros

Dosztányi

Magyar

et al. 2014

Computational Methods to Study the Structure and Dynamics of Biomolecules and Biomolecular Processes

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Abstract. Intrinsically unstructured/disordered proteins (IUPs/IDPs) exist as highly flexible conformational ensembles without adopting a stable three-dimensional structure. Experimental and bioinformatical studies in the past two decades have shown that these proteins play a central role in various signaling and regulatory processes. Accordingly, their frequency in higher eukaryotes reaches high proportions and their malfunction can be connected to a wide variety of diseases. Recognizing the biological importance of these proteins motivated researchers to understand various aspects of disordered proteins and protein segments from the viewpoint of biochemistry, molecular biology and pharmacology. In general, IDPs are difficult to study experimentally because of the lack of a unique structure in the isolated form. Nevertheless, various bioinformatics tools developed over the last few years enable their identification and characterization using only the amino acid sequence. In this chapter -after a brief introduction to IDPs in generalwe present a small survey of current methods aimed at identifying disordered proteins or protein segments, focusing on those that are publicly available as web servers. We also discuss in more detail approaches that predict disordered regions and specific regions involved in protein binding by modeling the physical background of protein disorder. Furthermore, we argue that the heterogeneity of disordered segments needs to be taken into account for a better understanding of protein disorder and the correct use and interpretation of the output of disorder prediction algorithms.

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Dynamic interactions of proteins in complex networks: a more structured view

Cited by 105 publications

References 118 publications

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

A sequence-specific transcription activator motif and powerful synthetic variants that bind Mediator using a fuzzy protein interface

Bioinformatical Approaches to Unstructured/Disordered Proteins and Their Interactions

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