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posted 19. November 2005 21:23
Systematic Discovery of New Recognition Peptides Mediating Protein Interaction Networks
Victor Neduva, Rune Linding, Isabelle Su-Angrand1, Alexander Stark1, Federico de Masi, Toby J. Gibson, Joe Lewis1, Luis Serrano, Robert B. Russell,
Abstract
Many aspects of cell signalling, trafficking, and targeting are governed by interactions between globular protein domains and short peptide segments. These domains often bind multiple peptides that share a common sequence pattern, or “linear motif” (e.g., SH3 binding to PxxP). Many domains are known, though comparatively few linear motifs have been discovered. Their short length (three to eight residues), and the fact that they often reside in disordered regions in proteins makes them difficult to detect through sequence comparison or experiment. Nevertheless, each new motif provides critical molecular details of how interaction networks are constructed, and can explain how one protein is able to bind to very different partners. Here we show that binding motifs can be detected using data from genome-scale interaction studies, and thus avoid the normally slow discovery process. Our approach based on motif over-representation in non-homologous sequences, rediscovers known motifs and predicts dozens of others. Direct binding experiments reveal that two predicted motifs are indeed protein-binding modules: a DxxDxxxD protein phosphatase 1 binding motif with a KD of 22 μM and a VxxxRxYS motif that binds Translin with a KD of 43 μM. We estimate that there are dozens or even hundreds of linear motifs yet to be discovered that will give molecular insight into protein networks and greatly illuminate cellular processes.
Methodology
Our central hypothesis is that proteins with a common interaction partner will share a feature that mediates binding, either a domain or a linear motif. In the absence of a shared domain, a linear motif could well be the only common sequence feature and might thus be detectable simply by virtue of over-representation, which is the basis of our approach.
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Read the full research article at PLoS Biology
Academic Editor: Rowena Matthews, University of Michigan, United States of America
Received: August 9, 2005; Accepted: September 27, 2005; Published: November 15, 2005
*To whom correspondence should be addressed. E-mail: russell@embl.de
Citation: Neduva V, Linding R, Su-Angrand I, Stark A, Masi Fd, et al. (2005) Systematic Discovery of New Recognition Peptides Mediating Protein Interaction Networks. PLoS Biol 3(12): e405
DOI: 10.1371/journal.pbio.0030405
Copyright: © 2005 Neduva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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