72 research outputs found
PTMcode: a database of known and predicted functional associations between post-translational modifications in proteins
Post-translational modifications (PTMs) are involved in the regulation and structural stabilization of eukaryotic proteins. The combination of individual PTM states is a key to modulate cellular functions as became evident in a few well-studied proteins. This combinatorial setting, dubbed the PTM code, has been proposed to be extended to whole proteomes in eukaryotes. Although we are still far from deciphering such a complex language, thousands of protein PTM sites are being mapped by high-throughput technologies, thus providing sufficient data for comparative analysis. PTMcode (http://ptmcode.embl.de) aims to compile known and predicted PTM associations to provide a framework that would enable hypothesis-driven experimental or computational analysis of various scales. In its first release, PTMcode provides PTM functional associations of 13 different PTM types within proteins in 8 eukaryotes. They are based on five evidence channels: a literature survey, residue co-evolution, structural proximity, PTMs at the same residue and location within PTM highly enriched protein regions (hotspots). PTMcode is presented as a protein-based searchable database with an interactive web interface providing the context of the co-regulation of nearly 75 000 residues in >10 000 proteins
Evaluation of potential miRNA sponge effects of SARS genomes in human
: To date the coronavirus family is composed of seven different viruses which were commonly known as cold viruses until the appearance of the severe acute respiratory coronavirus (SARS-CoV) in 2002, the middle east respiratory syndrome coronavirus (MERS) in 2012 and the severe acute respiratory coronavirus 2 (SARS-CoV-2) which caused the COVID-19 global pandemic in 2019. Using bioinformatic approaches we tested the potential interactions of human miRNAs, expressed in pulmonary epithelial cells, with the available coronavirus genomes. Putative miRNA binding sites were then compared between pathogenic and non pathogenic virus groups. The pathogenic group shares 6 miRNA binding sites that can be potentially involved in the sequestration of miRNAs already known to be associated with deep vein thrombosis. We then analysed ∼100k SARS-CoV-2 variant genomes for their potential interaction with human miRNAs and this study highlighted a group of 97 miRNA binding sites which is present in all the analysed genomes. Among these, we identified 6 miRNA binding sites specific for SARS-CoV-2 and the other two pathogenic viruses whose down-regulation has been seen associated with deep vein thrombosis and cardiovascular diseases. Interestingly, one of these miRNAs, namely miR-20a-5p, whose expression decreases with advancing age, is involved in cytokine signaling, cell differentiation and/or proliferation. We hypothesize that depletion of poorly expressed miRNA could be related with disease severity
PTMcode v2: a resource for functional associations of post-translational modifications within and between proteins
The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300 000 experimentally verified PTMs (>1 300 000 propagated) of 69 types extracting the post-translational regulation of >100 000 proteins and >100 000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs
MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits
Numerous lines of evidence have shown that the interaction between the nuclear and mitochondrial genomes ensures the efficient functioning of the OXPHOS complexes, with substantial implications in bioenergetics, adaptation, and disease. Their interaction is a fascinating and complex trait of the eukaryotic cell that MitImpact explores with its third major release. MitImpact expands its collection of genomic, clinical, and functional annotations of all non-synonymous substitutions of the human mitochondrial genome with new information on putative Compensated Pathogenic Deviations and co-varying amino acid sites of the Respiratory Chain subunits. It further provides evidence of energetic and structural residue compensation by techniques of molecular dynamics simulation. MitImpact is freely accessible at http://mitimpact.css-mendel.it
Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome
Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A is the disease causative gene of type 2 Kabuki Syndrome, a rare multisystem disease. While nonsense mutations and short insertions/deletions are known to trigger pathogenic mechanisms, the functional effects of missense mutations are still uncharacterized. In this study, we demonstrate that a selected set of missense mutations significantly hamper the interaction between KDM6A and the histone H3, by modifying the dynamics of the linker domain, and then causing a loss of function effect
Phosfinder: a web server for the identification of phosphate-binding sites on protein structures
Phosfinder is a web server for the identification of phosphate binding sites in protein structures. Phosfinder uses a structural comparison algorithm to scan a query structure against a set of known 3D phosphate binding motifs. Whenever a structural similarity between the query protein and a phosphate binding motif is detected, the phosphate bound by the known motif is added to the protein structure thus representing a putative phosphate binding site. Predicted binding sites are then evaluated according to (i) their position with respect to the query protein solvent-excluded surface and (ii) the conservation of the binding residues in the protein family. The server accepts as input either the PDB code of the protein to be analyzed or a user-submitted structure in PDB format. All the search parameters are user modifiable. Phosfinder outputs a list of predicted binding sites with detailed information about their structural similarity with known phosphate binding motifs, and the conservation of the residues involved. A graphical applet allows the user to visualize the predicted binding sites on the query protein structure. The results on a set of 52 apo/holo structure pairs show that the performance of our method is largely unaffected by ligand-induced conformational changes. Phosfinder is available at http://phosfinder.bio.uniroma2.it
Thiol‐based redox sensing in the methyltransferase associated sensor kinase RdmS in Methanosarcina acetivorans
Thermal-mechanical behaviour of the hierarchical structure of human dental tissue
Human dental tissues are fascinating nano-structured hierarchical materials that combine organic and mineral phases in an intricate and ingenious way to obtain remarkable combinations of mechanical strength, thermal endurance, wear resistance and chemical stability. Attempts to imitate and emulate this performance have been made since time immemorial, in order to provide replacement (e.g. in dental prosthodontics) or to develop artificial materials with similar characteristics (e.g. light armour). The key objectives of the present project are to understand the structure-property relationships that underlie the integrity of natural materials, human dental tissues in particular, and the multi-scale architecture of mineralized tissues and its evolution under thermal treatment and mechanical loading. The final objective is to derive ideas for designing and manufacturing novel artificial materials serving biomimetic purposes. The objectives are achieved using the combination of a range of characterization techniques, with particular attention paid to the synchrotron X-ray scattering (Small- and Wide-Angle X-ray Scattering, SAXS and WAXS) and imaging techniques (Micro Computed Tomography), as well as microscopy techniques such as Environmental Scanning Electron Microscopy (ESEM), Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM). Mechanical properties were characterized by nanoindentation and photoelasticity; and thermal analysis was carried out via thermogravimetric analysis (TGA). Experimental observations were critically examined and matched by advanced numerical simulation of the tissue under thermal-mechanical loading. SAXS and WAXS provided the initial basis for elucidating the structure-property relationships in human dentine and enamel through in situ experimentation. Four principal types of experiment were used to examine the thermal and mechanical behaviour of the hierarchical structure of human dental tissue and contributed to the Chapters of this thesis: (i) In situ elastic strain evolution under loading within the hydroxyapatite (HAp) in both dentine and enamel. An improved multi-scale Eshelby inclusion model was proposed taking into account the two-level hierarchical structure, and was validated against the experimental strain evaluation data. The achieved agreement indicates that the multi-scale model accurately reflects the structural arrangement of human dental tissue and its response to applied forces. (ii) The morphology of the dentine-enamel junction (DEJ) was examined by a range of techniques, including X-ray imaging and diffraction. The transition of mechanical properties across the DEJ was evaluated by the high resolution mapping and in situ compression measurement, followed by a brief description of the thermal behaviour of DEJ. The results show that DEJ is a narrow band of material with graded structure and mechanical properties, rather than a discrete interface. (iii) Further investigation regarding the thermo-mechanical structure-property relationships in human dental tissues was carried out by nanoindentation mapping of the nano-mechanical properties in ex situ thermally treated dental tissues. (iv) In order to understand the details of the thermal behaviour, in situ heat treatment was carried out on both human dental tissues and synthetic HAp crystallites. For the first time the in situ ultrastructural alteration of natural and synthetic HAp crystallites was captured in these experiments. The results presented in this thesis contribute to the fundamental understanding of the structure-property integrity mechanisms of natural materials, human dental tissues in particular. These results were reported in several first author publications in peer-reviewed journals, conference proceedings, and a book chapter.</p
Estudo Comparativo entre Densidade Básica e Penetração do Pilodyn em Espécies/Procedências de Pinus Centro-Americanos em três locais dos Cerrados.
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