Computational identification and analysis of protein short linear motifs

Davey, Norman E.; Edwards, Richard J.; Shields, Denis C.

doi:10.2741/3647

Cited by 30 publications

(31 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our approach for identifying short linear motifs is different from other computational methods designed for this goal (68). Two other bioinformatic approaches involve either the classification of matches to a known consensus (69) or the prediction of a consensus given known co-regulation (20, 70–73), both of which rely on previously obtained experimental data.…”

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions

et al. 2012

View full text Add to dashboard Cite

At least 30% of human proteins are thought to contain intrinsically disordered regions, which lack stable structural conformation. Despite lacking enzymatic functions and having few protein domains, disordered regions are functionally important for protein regulation and contain short linear motifs (short peptide sequences involved in protein-protein interactions), but in most disordered regions, the functional amino acid residues remain unknown. We searched for evolutionarily conserved sequences within disordered regions according to the hypothesis that conservation would indicate functional residues. Using a phylogenetic hidden Markov model (phylo-HMM), we made accurate, specific predictions of functional elements in disordered regions even when these elements are only two or three amino acids long. Among the conserved sequences that we identified were previously known and newly identified short linear motifs, and we experimentally verified key examples, including a motif that may mediate interaction between protein kinase Cbk1 and its substrates. We also observed that hub proteins, which interact with many partners in a protein interaction network, are highly enriched in these conserved sequences. Our analysis enabled the systematic identification of the functional residues in disordered regions and suggested that at least 5% of amino acids in disordered regions are important for function.

show abstract

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In this mechanism loosely structured protein segments reach out and bind their partners from larger distances due to their many exposed protein interaction motifs. Since short linear protein interaction motifs [45], [46], posttranslational modification sites [47], [48], and tissue-specific disordered binding regions of splice variants [49], [50], usually reside in disordered protein segments, these regions could be especially important in facilitating specific binding to partner proteins and in displaying important regulatory roles [21], [38]. All the above mentioned characteristics of disordered regions, along with other advantages they provide – such as their conformational freedom and their ability to bind many interactions partners (moonlighting [51]) – make them excellent candidates for the efficient assembly [52] and transport of macroscopic organelles.…”

Section: Introductionmentioning

confidence: 99%

Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways

2013

View full text Add to dashboard Cite

Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles, while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more disordered (∼23%) than the other two, COPI (∼9%) and COPII (∼8%). We show that this structural phenomenon enhances the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of structural disorder in vesicle trafficking and suggest major roles for this structural property in shaping the differences of evolutionary adaptability in the three routes.

show abstract

“…In fact, the biological information of a protein sequence appears to reside in short aa strings. (31) A minimotif of only five residues can determine or inhibit essential cellular functions and processes such as cell adhesion and nerve regeneration, (32,33) apoptosis, (34) cancer cell proliferation (35) or migration, (36) thrombin activity, (37) and angiogenesis. (38) Moreover, it is well known that a pentapeptide represents a minimal recognition unit at the basis of the immune response, (39,40) and has an immunotherapeutic potential.…”

Section: Resultsmentioning

confidence: 99%

A peptide talk between JC virus and the human host: from silent infection to autoimmunity

Lucchese¹

2012

Immunopharmacology and Immunotoxicology

View full text Add to dashboard Cite

Analysis of JC virus (JCV) polyprotein for peptide sharing with the human proteome reveals that the virus has hundreds of pentapeptide sequences in common with the human proteins. The datum is interesting in light of the fundamental role exerted by short amino acid sequences in protein-protein interactions and, consequently, in biochemical reactions and immune recognition. Searching for new approaches to understand the JCV infection scenarios, from the immunoevasion phenomenon underlying the viral asymptomatic stay in the human host to the (re)activation phase and associated pathogenic sequelae, the present study describes the diffuse pentapeptide communication network between JCV and the human host.

show abstract

Computational identification and analysis of protein short linear motifs

Cited by 30 publications

References 162 publications

Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions

Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions

Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways

A peptide talk between JC virus and the human host: from silent infection to autoimmunity

Contact Info

Product

Resources

About