Contextual specificity in peptide-mediated protein interactions.

Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usua...

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Autores principales:	Amelie Stein, Patrick Aloy
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5ab3396bb0e14e11905c9cc154e83275
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spelling	oai:doaj.org-article:5ab3396bb0e14e11905c9cc154e832752021-11-25T06:11:49ZContextual specificity in peptide-mediated protein interactions.1932-620310.1371/journal.pone.0002524https://doaj.org/article/5ab3396bb0e14e11905c9cc154e832752008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18596940/?tool=EBIhttps://doaj.org/toc/1932-6203Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks.Amelie SteinPatrick AloyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 7, p e2524 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amelie Stein Patrick Aloy Contextual specificity in peptide-mediated protein interactions.
description	Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks.
format	article
author	Amelie Stein Patrick Aloy
author_facet	Amelie Stein Patrick Aloy
author_sort	Amelie Stein
title	Contextual specificity in peptide-mediated protein interactions.
title_short	Contextual specificity in peptide-mediated protein interactions.
title_full	Contextual specificity in peptide-mediated protein interactions.
title_fullStr	Contextual specificity in peptide-mediated protein interactions.
title_full_unstemmed	Contextual specificity in peptide-mediated protein interactions.
title_sort	contextual specificity in peptide-mediated protein interactions.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/5ab3396bb0e14e11905c9cc154e83275
work_keys_str_mv	AT ameliestein contextualspecificityinpeptidemediatedproteininteractions AT patrickaloy contextualspecificityinpeptidemediatedproteininteractions
_version_	1718414042258735104

Contextual specificity in peptide-mediated protein interactions.

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