Biology subjects

Garcia-Bonete, M.-J.

Publications and source records attributed to Garcia-Bonete, M.-J..

6 recordsLinked to original sources

bioRxiv2025

Functional Group Composition: The Blueprint for Protein Interactions

Understanding the complex landscape of protein interactions, especially those involving intrinsically disordered proteins (IDPs), is fundamental yet challenging due to their structural heterogeneity and flexibility. Traditional sequence-based homology methods frequently fall short in characterizing IDP functions and interactions. Here, we present a novel approach leveraging supervised and unsupervised machine learning techniques, focusing exclusively on the compositional features of proteins. An Edmond-Ogston-inspired mixing model can reliably predict the degree of survivin (BIRC5) binding as a function of peptide composition alone, revealing a first interesting connection with the composition diagrams of chemical thermodynamics. By representing protein sequences through their functional group compositions, we demonstrate that specific compositions robustly predict binding interactions with survivin, an important human protein in cellular regulation pathways. Experimental validation via peptide microarray confirms the predictive power of our simplified compositional model, independent of exact amino acid sequences. Extending this method across the human proteome, we identified distinct compositional signatures correlating with survivin interactions and revealed fine grained biologically meaningful functional clusters based on compositional similarity. Our findings suggest a compositional blueprint underpinning protein interactions, offering a powerful, simplified framework to decode complex biological networks.

systems biology↗

bioRxiv2025

Degradation of the intestinal mucus layer by the ETEC protease EatA is species specific determined by the structure of the MUC2 mucin

Enterotoxigenic Escherichia coli (ETEC) infections are a leading cause of diarrheal illness, responsible for an estimated 100,000 deaths annually. ETEC pathogenesis is driven by various virulence factors, including toxins, adhesins, and noncanonical factors such as the protease EatA. The first line of host defense against intestinal pathogenic bacterial infections is the protective intestinal mucus layer. Here, we demonstrate the mechanism by which EatA facilitates access to the epithelial cell surface by degrading the core mucus component MUC2, thereby aiding to the infection. We identify the specific cleavage site region localized at the C-terminal of MUC2. EatAs protease activity depends on the interaction between two distinct domains, which are uniquely spaced in human MUC2, contributing to species specificity. This was confirmed using a novel chimeric mouse model solely expressing human MUC2, which allowed us to study the role of the mucus layer in the infection of human intestinal pathogens. These findings highlight how ETEC has adapted to specifically degrade the mucus layer of its human host.

molecular biology↗

bioRxiv2024

Survivin in synergy with BAF/SWI complex binds bivalent chromatin regions and activates DNA damage response in CD4+ T cells

This study explores a regulatory role of oncoprotein survivin on the bivalent regions of chromatin (BvCR) characterized by concomitant deposition of trimethylated lysine of histone H3 at position 4 (H3K4me3) and 27 (H3K27me3). Intersect between BvCR and chromatin sequences bound to survivin demonstrated their co-localization on cis-regulatory elements of genes which execute DNA damage control in primary human CD4+ cells. Survivin anchored BRG1-complex to BvCR to repress DNA damage repair genes in IFN{gamma}-stimulated CD4+ cells. In contrast, survivin inhibition shifted the functional balance of BvCR in favor of H3K4me3, which activated DNA damage recognition and repair. Co-expression of BRG1, survivin and IFN{gamma} in CD4+ cells of patients with rheumatoid arthritis identified arthritogenic BRG1hi cells abundant in autoimmune synovia. Immunomodulating drugs inhibited the subunits anchoring BRG1-complex to BvCR, which changed the arthritogenic profile. Together, this study demonstrates the function of BvCR in DNA damage control of CD4+ cells offering an epigenetic platform for survivin and BRG1-complex targeting interventions to combat autoimmunity. SummaryThis study shows that bivalent chromatin regions accommodate survivin which represses DNA repair enzymes in IFN{gamma}-stimulated CD4+ T cells. Survivin anchors BAF/SWI complex to these regions and supports autoimmune profile of T cells, providing novel targets for therapeutic intervention.

immunology↗

bioRxiv2024

Deciphering Peptide-Protein Interactions via Composition-Based Prediction: A Case Study with Survivin/BIRC5

In the realm of atomic physics and chemistry, composition emerges as the most powerful means of describing matter. Mendeleevs periodic table and chemical formulas, while not entirely free from ambiguities, provide robust approximations for comprehending the properties of atoms, chemicals, and their collective behaviours, which stem from the dynamic interplay of their constituents. Our study illustrates that protein-protein interactions follow a similar paradigm, wherein the composition of peptides plays a pivotal role in predicting their interactions with the protein survivin, using an elegantly simple model. An analysis of these predictions within the context of the human proteome not only illuminates the known cellular locations of survivin and its interaction partners, but also introduces novel insights into biological functionality. It becomes evident that an electrostatic- and primary structure-based descriptions fall short in predictive power, leading us to speculate that protein interactions are orchestrated by the collective dynamics of functional groups.

bioinformatics↗

bioRxiv2021

Chromatin binding of survivin regulates glucose metabolism in the IFN-g producing CD4+T cells

Interferon-gamma (IFN{gamma}) producing T cells develop metabolic adaptation required for their effector functions in tumour biology, autoimmunity and antiviral defence. Using sorted CD4+ cells we demonstrated that glycolytic switch and high glucose uptake in IFN{gamma}-producing cells was associated with survivin expression. Inhibition of survivin restored glycolysis by upregulating the transcription of phosphofructokinase PFKFB3 and reducing glucose uptake. Integration of the whole-genome sequencing of the chromatin immunoprecipitated with survivin with transcription changes in CD4+ cells after survivin inhibition revealed co-localization of survivin, IRF1 and SMAD3 in the regulatory elements paired to the differentially expressed genes. Western blot demonstrated direct binding of survivin to IRF1 and SMAD3. Functionally, inhibition of survivin repressed IFN{gamma} signalling and activated SMAD3-dependent protein remodelling, which resulted in the effector-to-memory transition of CD4+ cells. These findings demonstrate the key role of survivin in IFN{gamma}-dependent metabolic adaptation and identify survivin inhibition as an attractive strategy to counteract these effects.

immunology↗

bioRxiv2018

Patterns of anisotropic temperature factors in bovine trypsin crystals with and without 0.5 THz irradiation

Vibrational oscillations in amide and side chain groups are well studied in proteins, but these are not occupied at ambient temperatures and they have a short lifespan when infrared radiation is present. Active vibrational modes in proteins lie in the terahertz (THz) range at physiological temperatures, and their experimental descriptions of them in this range are lacking. In this paper, we present the effect of 0.5 THz irradiation on atomic displacement parameters (ADP) in bovine trypsin. The crystals were subjected to terahertz radiation in an alternating manner and two states of the crystals were recovered using X-ray crystallography. The clustering of ADPs uniquely identified atoms from the different crystals. The ADP similarities tended to develop between chemically similar atoms and between atoms of the catalytic triad. This pattern of ADP similarity is likely created by delocalized polar vibration modes rather than, as frequently assumed, elastic and rigid-body motions.

biophysics↗