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Stein A.,Barcelona Institute for Research in Biomedicine
PLoS computational biology | Year: 2010

Many biological responses to intra- and extracellular stimuli 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. These peptide stretches are often found in unstructured regions of proteins, and contain a consensus motif complementary to the interaction surface displayed by their binding partners. While most current methods for the de novo discovery of such motifs exploit their tendency to occur in disordered regions, our work here focuses on another observation: upon binding to their partner domain, motifs adopt a well-defined structure. Indeed, through the analysis of all peptide-mediated interactions of known high-resolution three-dimensional (3D) structure, we found that the structure of the peptide may be as characteristic as the consensus motif, and help identify target peptides even though they do not match the established patterns. Our analyses of the structural features of known motifs reveal that they tend to have a particular stretched and elongated structure, unlike most other peptides of the same length. Accordingly, we have implemented a strategy based on a Support Vector Machine that uses this features, along with other structure-encoded information about binding interfaces, to search the set of protein interactions of known 3D structure and to identify unnoticed peptide-mediated interactions among them. We have also derived consensus patterns for these interactions, whenever enough information was available, and compared our results with established linear motif patterns and their binding domains. Finally, to cross-validate our identification strategy, we scanned interactome networks from four model organisms with our newly derived patterns to see if any of them occurred more often than expected. Indeed, we found significant over-representations for 64 domain-motif interactions, 46 of which had not been described before, involving over 6,000 interactions in total for which we could suggest the molecular details determining the binding. Source

Avgustinova A.,Barcelona Institute for Research in Biomedicine
Nature Reviews Molecular Cell Biology | Year: 2016

Mammalian embryonic development is a tightly regulated process that, from a single zygote, produces a large number of cell types with hugely divergent functions. Distinct cellular differentiation programmes are facilitated by tight transcriptional and epigenetic regulation. However, the contribution of epigenetic regulation to tissue homeostasis after the completion of development is less well understood. In this Review, we explore the effects of epigenetic dysregulation on adult stem cell function. We conclude that, depending on the tissue type and the epigenetic regulator affected, the consequences range from negligible to stem cell malfunction and disruption of tissue homeostasis, which may predispose to diseases such as cancer. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

Hospital A.,Barcelona Institute for Research in Biomedicine
Nucleic acids research | Year: 2013

We present NAFlex, a new web tool to study the flexibility of nucleic acids, either isolated or bound to other molecules. The server allows the user to incorporate structures from protein data banks, completing gaps and removing structural inconsistencies. It is also possible to define canonical (average or sequence-adapted) nucleic acid structures using a variety of predefined internal libraries, as well to create specific nucleic acid conformations from the sequence. The server offers a variety of methods to explore nucleic acid flexibility, such as a colorless wormlike-chain model, a base-pair resolution mesoscopic model and atomistic molecular dynamics simulations with a wide variety of protocols and force fields. The trajectories obtained by simulations, or imported externally, can be visualized and analyzed using a large number of tools, including standard Cartesian analysis, essential dynamics, helical analysis, local and global stiffness, energy decomposition, principal components and in silico NMR spectra. The server is accessible free of charge from the mmb.irbbarcelona.org/NAFlex webpage. Source

Batlle E.,Barcelona Institute for Research in Biomedicine | Wilkinson D.G.,UK National Institute for Medical Research
Cold Spring Harbor Perspectives in Biology | Year: 2012

The establishment and maintenance of precisely organized tissues requires the formation of sharp borders between distinct cell populations. The maintenance of segregated cell populations is also required for tissue homeostasis in the adult, and deficiencies in segregation underlie the metastatic spreading of tumor cells. Three classes of mechanisms that underlie cell segregation and border formation have been uncovered. The first involves differences in cadherin- mediated cell-cell adhesion that establishes interfacial tension at the border between distinct cell populations. A second mechanism involves the induction of actomyosin-mediated contraction by intercellular signaling, such that cortical tension is generated at the border. Third, activation of Eph receptors and ephrins can lead to both decreased adhesion by triggering cleavage of E-cadherin, and to repulsion of cells by regulation of the actin cytoskeleton, thus preventing intermingling between cell populations. These mechanisms play crucial roles at distinct boundaries during development, and alterations in cadherin or Eph/ephrin expression have been implicated in tumor metastasis. © 2011 Cold Spring Harbor Laboratory Press. Source

Luders J.,Barcelona Institute for Research in Biomedicine
Nature Cell Biology | Year: 2012

The pericentriolar material (PCM), the microtubule-organizing component of the centrosome, contains a multitude of proteins and is commonly described as an amorphous cloud surrounding the centrioles. However, the days of the PCM as an unstructured matrix are numbered. Using super-resolution microscopy, several reports have now revealed remarkable domain organization within the PCM. © 2012 Macmillan Publishers Limited. Source

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