Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein-protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein-protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.

https://www.zora.uzh.ch/id/eprint/165500/1/30476243.pdf

STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.

The many functional partnerships and interactions that occur between proteins are at the core of cellular processing and their systematic characterization helps to provide context in molecular systems biology. However, known and predicted interactions are scattered over multiple resources, and the available data exhibit notable differences in terms of quality and completeness. The STRING database (http://string-db.org) aims to provide a critical assessment and integration of protein-protein interactions, including direct (physical) as well as indirect (functional) associations. The new version 10.0 of STRING covers more than 2000 organisms, which has necessitated novel, scalable algorithms for transferring interaction information between organisms. For this purpose, we have introduced hierarchical and self-consistent orthology annotations for all interacting proteins, grouping the proteins into families at various levels of phylogenetic resolution. Further improvements in version 10.0 include a completely redesigned prediction pipeline for inferring protein-protein associations from co-expression data, an API interface for the R computing environment and improved statistical analysis for enrichment tests in user-provided networks.

/pdf/string-v10-protein-protein-interaction-networks-integrated-2gg77rxec0.pdf

STRING v10: protein–protein interaction networks, integrated over the tree of life

A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein-protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein-protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/.

/pdf/the-string-database-in-2017-quality-controlled-protein-1u6rx6raii.pdf

The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible.

UniProt: A worldwide hub of protein knowledge

The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently.

/pdf/the-reactome-pathway-knowledgebase-gtcb4s9ynr.pdf

The Reactome Pathway Knowledgebase.

Impact of calcium ions on the structural and dynamic properties of heparin oligosaccharides by computational analysis

Extracellular matrices (ECMs), as dynamic threedimensional networks of macromolecules, play key roles in the structural organization of tissues, cell–cell and cell–matrix interactions affecting cell functional properties and behavior, gene expression, tissue remodeling, and cell signaling. Research on the mechanisms that the ECM modulates cell functions will help to develop therapeutic agents targeting several serious diseases. This special issue addresses the ECM roles in cell functional properties, disease diagnosis, and pharmacological targeting/treatment approaches. Particularly, the importance of the sulfated hyaluronan in cancer, angiogenesis, and of hyaluronan in ECM pathobiology, immune responses, and cancer progression are reviewed by F. Spinelli et al. and D. Kokoretsis et al., respectively. The role of syndecan-1 in tumor progression using a 3D breast carcinoma model is highlighted by C. D'Arcy et al. A. Papadopoulou et al. show that the irradiation of human breast adipose-derived stem cells induces their premature senescence, decreases their differentiation capacity, and alters their expression of ECM components. The critical roles of thrombospondins in the development of human aortic aneurysms and their potential use as diagnostic tools and/or therapeutic targets are discussed by E. Plana et al. The ECM effectors and the biochemical pathways involved in the development and the progression of pseudoexfoliation syndrome are reviewed by S. Mastronikolis et al. ECM alteration and stem cell gene dysregulation associated with atheromatosis are discussed by S. Mylonas et al. The effects of steviol glycosides on gene expression by breast cancer cells, including syndecans-2 and -4 and CD44, is demonstrated by Velesiotis et al. We greatly appreciate the opportunity given by the Editor-in-Chief, Dr Stathis Gonos to collect important contributions on the dynamic roles of ECM, and Mrs Sofia Athanasopoulou for her guidance in all the steps of the preparation of this Special Issue. We do hope will be an informative collection and a driving force for the researchers in the ECM field.

Extracellular matrix: The dynamic structural and functional network in health and disease

Leishmaniasis is a detrimental disease causing serious changes in quality of life and some forms lead to death. The disease is spread by the parasite Leishmania transmitted by sandfly vectors and their primary hosts are vertebrates including humans. The pathogen penetrates host cells and secretes proteins (the secretome) to repurpose cells for pathogen growth and to alter cell signaling via host-pathogen Protein-Protein Interactions (PPIs). Here we present LeishMANIAdb, a database specifically designed to investigate how Leishmania virulence factors may interfere with host proteins. Since the secretomes of different Leishmania species are only partially characterized, we collected various experimental evidence and used computational predictions to identify Leishmania secreted proteins to generate a user-friendly unified web resource allowing users to access all information available on experimental and predicted secretomes. In addition, we manually annotated host-pathogen interactions of 211 proteins, and the localization/function of 3764 transmembrane (TM) proteins of different Leishmania species. We also enriched all proteins with automatic structural and functional predictions that can provide new insights in the molecular mechanisms of infection. Our database, available at https://leishmaniadb.ttk.hu may provide novel insights into Leishmania host-pathogen interactions and help to identify new therapeutic targets for this neglected disease.

/pdf/leishmaniadb-a-comparative-resource-for-leishmania-proteins-2buq1tat.pdf

LeishMANIAdb: a comparative resource for Leishmania proteins

It is generally accepted that the folding of collagen triple helical domains occur from the C-terminus toward the N-terminus by a “zipper” mechanism. The regions at the C-terminus of the triple helices must therefore play a critical role in the processes of chain recognition and assembly to get the proper stoichiometries and of chain registration to align the chains for the folding of the triple helix. Examination of these regions reveals a broad diversity of structures and suggests that different mechanisms of assembly are used in the various collagen and collagen-like molecules. We review here three different mechanisms that have recently come to light. The collectins, a group of serum proteins containing collagen-like triple helical domains, are assembled through hydrophobic interactions in a tripleα helix. Collagens VIII and X, C1q and several related proteins contain homologous C-terminal domains that are characterized by aβ-pleated sheet structure. They assemble through very strong hydrophobic interactions that probably involve an “aromatic zipper”. Collagens IX, XII and XIV fibril associated collagen with interrupted triple helices (FACITs), are assembled by a mechanism in which both the C-terminal triple helix and a very short cysteine-containing sequence are involved.

Mechanisms of Collagen Trimer Assembly

Syndecans are transmembrane heparan sulfate proteoglycans present on most mammalian cell surfaces. They have a long evolutionary history, a single syndecan gene being expressed in bilaterian invertebrates. Syndecans have attracted interest because of their potential roles in development and disease, including vascular diseases, inflammation and various cancers. Recent structural data is providing important insights into their functions, which are complex, involving both intrinsic signaling through cytoplasmic binding partners and co-operative mechanisms where syndecans form a signaling nexus with other receptors such as integrins and tyrosine kinase growth factor receptors. While the cytoplasmic domain of syndecan-4 has a well-defined dimeric structure, the syndecan ectodomains are intrinsically disordered, which is linked to a capacity to interact with multiple partners. However, it remains to fully establish the impact of glycanation and partner proteins on syndecan core protein conformations. Genetic models indicate that a conserved property of syndecans links the cytoskeleton to calcium channels of the transient receptor potential class, compatible with roles as mechanosensors. In turn, syndecans influence actin cytoskeleton organization to impact motility, adhesion and the extracellular matrix environment. Syndecan clustering with other cell surface receptors into signaling microdomains has relevance to tissue differentiation in development, for example in stem cells, but also in disease where syndecan expression can be markedly up-regulated. Since syndecans have potential as diagnostic and prognostic markers as well as possible targets in some forms of cancer, it remains important to unravel structure/function relationships in the four mammalian syndecans. 

Sylvie Ricard-Blum

Papers

Impact of calcium ions on the structural and dynamic properties of heparin oligosaccharides by computational analysis

Extracellular matrix: The dynamic structural and functional network in health and disease

LeishMANIAdb: a comparative resource for Leishmania proteins

Mechanisms of Collagen Trimer Assembly

Conformations, interactions and functions of intrinsically disordered syndecans