53 research outputs found
Relationships between predicted moonlighting proteins, human diseases, and comorbidities from a network perspective
International audienceMoonlighting proteins are a subset of multifunctional proteins characterized by their multiple, independent, and unrelated biological functions. We recently set up a large-scale identification of moonlighting proteins using a protein-protein interaction (PPI) network approach. We established that 3% of the current human interactome is composed of predicted moonlighting proteins. We found that disease-related genes are over-represented among those candidates. Here, by comparing moonlighting candidates to non-candidates as groups, we further show that (7 they are significantly involved in more than one disease, (ii) they contribute to complex rather than monogenic diseases, (iii) the diseases in which they are involved are phenotypically different according to their annotations, finally, (iv) they are enriched for diseases pairs showing statistically significant comorbidity patterns based on Medicare records. Altogether, our results suggest that some observed comorbidities between phenotypically different diseases could be due to a shared protein involved in unrelated biological processes
Phospho3D: a database of three-dimensional structures of protein phosphorylation sites
Phosphorylation is the most common protein post-translational modification. Phosphorylated residues (serine, threonine and tyrosine) play critical roles in the regulation of many cellular processes. Since the amount of data produced by screening assays is growing continuously, the development of computational tools for collecting and analysing experimental data has become a pivotal task for unravelling the complex network of interactions regulating eukaryotic cell life. Here we present Phospho3D, , a database of 3D structures of phosphorylation sites, which stores information retrieved from the phospho.ELM database and is enriched with structural information and annotations at the residue level. The database also collects the results of a large-scale structural comparison procedure providing clues for the identification of new putative phosphorylation sites
pdbFun: mass selection and fast comparison of annotated PDB residues
pdbFun () is a web server for structural and functional analysis of proteins at the residue level. pdbFun gives fast access to the whole Protein Data Bank (PDB) organized as a database of annotated residues. The available data (features) range from solvent exposure to ligand binding ability, location in a protein cavity, secondary structure, residue type, sequence functional pattern, protein domain and catalytic activity. Users can select any residue subset (even including any number of PDB structures) by combining the available features. Selections can be used as probe and target in multiple structure comparison searches. For example a search could involve, as a query, all solvent-exposed, hydrophylic residues that are not in alpha-helices and are involved in nucleotide binding. Possible examples of targets are represented by another selection, a single structure or a dataset composed of many structures. The output is a list of aligned structural matches offered in tabular and also graphical format
iSPOT: A Web Tool for the Analysis and Recognition of Protein Domain Specificity
Methods that aim at predicting interaction partners are very likely to play an important
role in the interpretation of genomic information. iSPOT (iSpecificity Prediction Of
Target) is a web tool (accessible at http://cbm.bio.uniroma2.it/iSPOT) developed for the
prediction of protein-protein interaction mediated by families of peptide recognition
modules. iSPOT accesses a database of position specific residue-residue interaction
frequencies for members of the SH3 and PDZ protein domain families. The software
utilises this database to provide a score for any potential domain peptide interaction
Development of Computational Tools for the Inference of Protein Interaction Specificity Rules and Functional Annotation Using Structural Information
Relatively few protein structures are known, compared to the enormous amount of sequence data produced in the sequencing of different genomes, and relatively few
protein complexes are deposited in the PDB with respect to the great amount of
interaction data coming from high-throughput experiments (two-hybrid or affinity
purification of protein complexes and mass spectrometry). Nevertheless, we can rely
on computational techniques for the extraction of high-quality and information-rich
data from the known structures and for their spreading in the protein sequence space.
We describe here the ongoing research projects in our group: we analyse the protein
complexes stored in the PDB and, for each complex involving one domain belonging
to a family of interaction domains for which some interaction data are available, we
can calculate its probability of interaction with any protein sequence. We analyse the
structures of proteins encoding a function specified in a PROSITE pattern, which
exhibits relatively low selectivity and specificity, and build extended patterns. To
this aim, we consider residues that are well-conserved in the structure, even if their
conservation cannot easily be recognized in the sequence alignment of the proteins
holding the function. We also analyse protein surface regions and, through the
annotation of the solvent-exposed residues, we annotate protein surface patches via a
structural comparison performed with stringent parameters and independently of the
residue order in the sequence. Local surface comparison may also help in identifying
new sequence patterns, which could not be highlighted with other sequence-based
methods
STITCH 2: an interaction network database for small molecules and proteins
Over the last years, the publicly available knowledge on interactions between small molecules and proteins has been steadily increasing. To create a network of interactions, STITCH aims to integrate the data dispersed over the literature and various databases of biological pathways, drugātarget relationships and binding affinities. In STITCH 2, the number of relevant interactions is increased by incorporation of BindingDB, PharmGKB and the Comparative Toxicogenomics Database. The resulting network can be explored interactively or used as the basis for large-scale analyses. To facilitate links to other chemical databases, we adopt InChIKeys that allow identification of chemicals with a short, checksum-like string. STITCH 2.0 connects proteins from 630 organisms to over 74 000 different chemicals, including 2200 drugs. STITCH can be accessed at http://stitch.embl.de/
Computation of significance scores of unweighted Gene Set Enrichment Analyses
<p>Abstract</p> <p>Background</p> <p>Gene Set Enrichment Analysis (GSEA) is a computational method for the statistical evaluation of sorted lists of genes or proteins. Originally GSEA was developed for interpreting microarray gene expression data, but it can be applied to any sorted list of genes. Given the gene list and an arbitrary biological category, GSEA evaluates whether the genes of the considered category are randomly distributed or accumulated on top or bottom of the list. Usually, significance scores (p-values) of GSEA are computed by nonparametric permutation tests, a time consuming procedure that yields only estimates of the p-values.</p> <p>Results</p> <p>We present a novel dynamic programming algorithm for calculating exact significance values of unweighted Gene Set Enrichment Analyses. Our algorithm avoids typical problems of nonparametric permutation tests, as varying findings in different runs caused by the random sampling procedure. Another advantage of the presented dynamic programming algorithm is its runtime and memory efficiency. To test our algorithm, we applied it not only to simulated data sets, but additionally evaluated expression profiles of squamous cell lung cancer tissue and autologous unaffected tissue.</p
An integer linear programming approach for finding deregulated subgraphs in regulatory networks
Deregulation of cell signaling pathways plays a crucial role in the development of tumors. The identification of such pathways requires effective analysis tools that facilitate the interpretation of expression differences. Here, we present a novel and highly efficient method for identifying deregulated subnetworks in a regulatory network. Given a score for each node that measures the degree of deregulation of the corresponding gene or protein, the algorithm computes the heaviest connected subnetwork of a specified size reachable from a designated root node. This root node can be interpreted as a molecular key player responsible for the observed deregulation. To demonstrate the potential of our approach, we analyzed three gene expression data sets. In one scenario, we compared expression profiles of non-malignant primary mammary epithelial cells derived from BRCA1 mutation carriers and of epithelial cells without BRCA1 mutation. Our results suggest that oxidative stress plays an important role in epithelial cells of BRCA1 mutation carriers and that the activation of stress proteins may result in avoidance of apoptosis leading to an increased overall survival of cells with genetic alterations. In summary, our approach opens new avenues for the elucidation of pathogenic mechanisms and for the detection of molecular key players
Protein Phosphorylation in Health and Disease
Protein phosphorylation is one of the most abundant reversible post-translational modifications in eukaryotes. It is involved in virtually all cellular processes by regulating protein function, localization and stability and by mediating protein-protein interactions. Furthermore, aberrant protein phosphorylation is implicated in the onset and progression of human diseases such as cancer and neurodegenerative disorders. In the last years, tens of thousands of in vivo phosphorylation events have been identified by large-scale quantitative phospho-proteomics experiment suggesting that a large fraction of the proteome might be regulated by phosphorylation. This data explosion is increasingly enabling the development of computational approaches, often combined with experimental validation, aiming at prioritizing phosphosites and assessing their functional relevance. Some computational approaches also address the inference of specificity determinants of protein kinases/phosphatases and the identification of phosphoresidue recognition domains. In this context, several challenging issues are still open regarding phosphorylation, including a better understanding of the interplay between phosphorylation and allosteric regulation, agents and mechanisms disrupting or promoting abnormal phosphorylation in diseases, the identification and modulation of novel phosphorylation inhibitors, and so forth. Furthermore, the determinants of kinase and phosphatase recognition and binding specificity are still unknown in several cases, as well as the impact of disease mutations on phosphorylation-mediated signaling. The articles included in this Research Topic illustrate the very diverse aspects of phosphorylation, ranging from structural changes induced by phosphorylation to the peculiarities of phosphosite evolution. Some also provide a glimpse into the huge complexity of phosphorylation networks and pathways in health and disease, and underscore that a deeper knowledge of such processes is essential to identify disease biomarkers, on one hand, and design more effective therapeutic strategies, on the other
A prismatic view of protein phosphorylation in health and disease
International audienceThe paramount relevance of protein phosphorylation in health and disease motivated us to gather several contributions from experts working in this area in order to portray the recent developments in the field. Our effort and the effort of 54 authors with their 12 contributions gave rise to this Research Topic, which represents a valuable forum where phosphorylation is discussed from different angles, including bioinformatics approaches and experimental methods that are currently used to decipher the complex mechanisms underlying this bewitching post-translational modification (PTM). The articles collected in this Research Topic illustrate very diverse aspects of phosphorylation, such as its biological effects and induced structural changes, the role of kinases and phosphatases as therapeutic targets, the use of phosphorylation profiles as biomarkers, how phosphorylation dys-regulation may cause disease, and more
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