The IMEx consortium is an international collaboration between major public interaction data providers to share curation effort and make a non-redundant set of protein interactions available in a single search interface on a common website (www.imexconsortium.org). Common curation rules have been developed and a central registry is used to manage the selection of articles to enter into the dataset. The advantages of such a service to the user, quality control measures adopted and data distribution practices are discussed.

To study proteins in the context of a cellular system, it is essential that the molecules with which a protein interacts are identified and the functional consequence of each interaction is understood. A plethora of resources now exist to capture molecular interaction data from the many laboratories generating

The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.

MatrixDB (http://matrixdb.ibcp.fr) is a freely available database focused on interactions established by extracellular proteins and polysaccharides. Only few databases report protein–polysaccharide interactions and, to the best of our knowledge, there is no other database of extracellular interactions. MatrixDB takes into account the multimeric nature of several extracellular protein families for the curation of interactions, and reports interactions with individual polypeptide chains or with multimers, considered as permanent complexes, when appropriate. MatrixDB is a member of the International Molecular Exchange consortium (IMEx) and has adopted the PSI-MI standards for the curation and the exchange of interaction data. MatrixDB stores experimental data from our laboratory, data from literature curation, data imported from IMEx databases, and data from the Human Protein Reference Database. MatrixDB is focused on mammalian interactions, but aims to integrate interaction datasets of model organisms when available. MatrixDB provides direct links to databases recapitulating mutations in genes encoding extracellular proteins, to UniGene and to the Human Protein Atlas that shows expression and localization of proteins in a large variety of normal human tissues and cells. MatrixDB allows researchers to perform customized queries and to build tissue- and disease-specific interaction networks that can be visualized and analyzed with Cytoscape or Medusa.

Summary: MatrixDB (http://matrixdb.ibcp.fr) is a database reporting mammalian protein–protein and protein–carbohydrate interactions involving extracellular molecules. It takes into account the full interaction repertoire of the extracellular matrix involving full-length molecules, fragments and multimers. The current version of MatrixDB contains 1972 interactions corresponding to 4412 experiments and involving 259 extracellular biomolecules.Availability: MatrixDB is freely available at http://matrixdb.ibcp.frContact: nicolas.thierry-mieg@imag.fr; s.ricard-blum@ibcp.frSupplementary information: Supplementary data are available at Bioinformatics online.

Endostatin is an endogenous inhibitor of angiogenesis. Although several endothelial cell surface molecules have been reported to interact with endostatin, its molecular mechanism of action is not fully elucidated. We used surface plasmon resonance assays to characterize interactions between endostatin, integrins, and heparin/heparan sulfate. ␣5␤1 and ␣v␤3 integrins form stable complexes with immobilized endostatin (K D ‫؍‬ ϳ1.8 ؋ 10؊8 M, two-state model). Two arginine residues (Arg 27 and Arg 139 ) are crucial for the binding of endostatin to integrins and to heparin/heparan sulfate, suggesting that endostatin would not bind simultaneously to integrins and to heparan sulfate. Experimental data and molecular modeling support endostatin binding to the headpiece of the ␣v␤3 integrin at the interface between the ␤-propeller domain of the ␣v subunit and the ␤A domain of the ␤3 subunit. In addition, we report that ␣5␤1 and ␣v␤3 integrins bind to heparin/heparan sulfate. The ectodomain of the ␣5␤1 integrin binds to haparin with high affinity (K D ‫؍‬ 15.5 nM). The direct binding between integrins and heparin/heparan sulfate might explain why both heparan sulfate and ␣5␤1 integrin are required for the localization of endostatin in endothelial cell lipid rafts.

Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It binds to heparin/heparan sulfate and to a number of proteins, but its molecular mechanisms of action are not fully elucidated. We have used surface plasmon resonance (SPR) arrays to identify new partners of endostatin, and to give further insights on its molecular mechanism of action. New partners of endostatin include glycosaminoglycans (chondroitin and dermatan sulfate), matricellular proteins (thrombospondin-1 and SPARC), collagens (I, IV, and VI), the amyloid peptide A␤-(1-42), and transglutaminase-2. The biological functions of the endostatin network involve a number of extracellular proteins containing epidermal growth factor and epidermal growth factor-like domains, and able to bind calcium. Depending on the trigger event, and on the availability of its members in a given tissue at a given time, the endostatin network might be involved either in the control of angiogenesis, and tumor growth, or in neurogenesis and neurodegenerative diseases.Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It inhibits angiogenesis and tumor growth (1-3). The effect of endostatin depends on its concentration (4, 5), on the length of exposure (6), on the type of endothelial cells (7), and on the growth factor inducing cell proliferation (fibroblast growth factor 2 or VEGF) 3 (8, 9). Endostatin binds to several membrane proteins including ␣5␤1 and ␣v␤3 integrins (10, 11), heparan sulfate proteoglycans (glypican-1 and -4) (12), and KDR/Flk1/VEGFR2 (13). We have previously characterized the binding of endostatin to heparan sulfate chains (9), and of endostatin to integrins (11). Furthermore, we have shown that ␣5␤1, ␣v␤3, and ␣v␤5 integrins bind to heparin/heparan sulfate (11).The broad molecular targets of endostatin suggest that multiple signaling systems are involved in mediation of its antiangiogenic action. Endostatin is a broad spectrum angiogenesis inhibitor that suppresses angiogenesis by blocking general mechanisms that govern endothelial cell growth (14), and initiates a complex network of signaling at the gene level (15). However, its molecular mechanism of action is still a matter of debate. An integrative view of the endostatin interaction network, including interactions between endostatin partners, is necessary to provide a clear understanding of how all these molecules work together to regulate angiogenesis, and tumor growth. This global approach places individual proteins into a functional context, and takes into account the fact that a single molecule such as endostatin can affect a wide range of other cell components. Indeed, most proteins and other components carry out their functions within a complex network of interactions and this approach based on protein-protein interaction networks has been developed for several years to give new clues on biological processes (16).This study ...