Interactome-wide prediction of short, disordered protein interaction motifs in humans

Edwards, Richard J.; Davey, Norman E.; O’Brien, Kevin T.; Shields, Denis C.

doi:10.1039/c1mb05212h

Cited by 33 publications

(55 citation statements)

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“…These regions often constitute functional, evolutionary and structural units (hence the name “domain”), and were thought to clearly differ from shorter elements, in particular linear motifs (3–11aa) [98], through their binding mode, affinity, and the fact that they arise by homologous descent rather than convergent evolution [95]. Reliable in silico identification of disordered domains would be a major advance because they mediate numerous (possibly thousands) of crucial but poorly characterized protein-protein interactions [99]. So far their detection has been restricted to domains longer than 20–30aa [95] because similarities detected between shorter regions are not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Detecting Remote Sequence Homology in Disordered Proteins: Discovery of Conserved Motifs in the N-Termini of Mononegavirales phosphoproteins

Karlin

Belshaw²

2012

PLoS ONE

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Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P) plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11–16aa), several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains) that could be detected simply by comparing orthologous proteins.

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Section: Discussionmentioning

confidence: 99%

Detecting Remote Sequence Homology in Disordered Proteins: Discovery of Conserved Motifs in the N-Termini of Mononegavirales phosphoproteins

Karlin

Belshaw²

2012

PLoS ONE

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“…Refs. [53][54][55][56][57][58][59][60][61]. Despite the considerable success of these approaches, in many cases, the stereochemical basis of even dominant specificity determinants remains obscure.…”

Section: Discussionmentioning

confidence: 99%

Stereochemical Determinants of C-terminal Specificity in PDZ Peptide-binding Domains

Amacher

Cushing

Bahl

et al. 2013

Journal of Biological Chemistry

101

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Background: PDZ-peptide binding specificities establish a complex network of protein-protein interactions in the cell. Results: Crystal structures of multiple PDZ-peptide complexes reveal distinct mechanisms for accommodating C-terminal ligand side chains. Conclusion: A residue in the PDZ "X⌽ 1 G⌽ 2 " signature sequence co-determines peptide carboxylate and C-terminal side-chain binding. Significance: Understanding the stereochemical determinants of peptide binding leads to an improved ability to predict PDZ interaction specificity.

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“…For one, such networks typically rely on highly specific and dynamic protein-protein interactions to be able to quickly transmit information within the cell (Smock and Gierasch 2009; Stein et al 2009). This is in part supported by the utilization of low affinity protein-protein interactions that involve compact (3–20 amino acid long), degenerate and evolvable modules that have been defined as S hort L inear M otifs (SLIMs) (Diella et al 2008; Davey et al 2012; Edwards et al 2012; Van Roey et al 2012; Weatheritt et al 2012a; Weatheritt et al 2012b; Van Roey et al 2013). Most of the binding specificity and affinity of a SLiM is embedded within a 2–5 residue-long core of amino acids.…”

Section: Introductionmentioning

confidence: 99%

“…Most of the binding specificity and affinity of a SLiM is embedded within a 2–5 residue-long core of amino acids. This paucity of amino acids limits the strength of SLiM-mediated interactions to a relatively low affinity range (1–150 μM) that supports transiency and reversibility of SLiM mediated protein-protein binding (Diella et al 2008; Davey et al 2012; Edwards et al 2012; Van Roey et al 2012; Weatheritt et al 2012a; Weatheritt et al 2012b; Van Roey et al 2013; Dinkel et al 2014). …”

Section: Introductionmentioning

confidence: 99%

The "Histone Mimicry" by Pathogens

Schaefer

Prinjha

et al. 2013

Cold Spring Harbor Symposia on Quantitative Biology

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One of the defining characteristics of human and animal viruses is their ability to suppress host antiviral responses. Viruses express proteins that impair the detection of viral nucleic acids by host pattern-recognition receptors, block signaling pathways that lead to the synthesis of type I interferons (IFN) and other cytokines, or prevent the activation of virus-induced genes. We have identified a novel mechanism of virus-mediated suppression of antiviral gene expression that relies on the presence of histone-like sequences (histone mimics) in viral proteins. We describe how viral histone mimics can interfere with key regulators of gene expression and contribute to the suppression of antiviral responses. We will also describe how viral histone mimics can facilitate the identification of novel mechanisms of antiviral gene regulation and lead to the development of drugs that employ histone mimicry for interference with gene expression during diseases.

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Interactome-wide prediction of short, disordered protein interaction motifs in humans

Cited by 33 publications

References 50 publications

Detecting Remote Sequence Homology in Disordered Proteins: Discovery of Conserved Motifs in the N-Termini of Mononegavirales phosphoproteins

Detecting Remote Sequence Homology in Disordered Proteins: Discovery of Conserved Motifs in the N-Termini of Mononegavirales phosphoproteins

Stereochemical Determinants of C-terminal Specificity in PDZ Peptide-binding Domains

The "Histone Mimicry" by Pathogens

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