Biology subjects

Faure, A.

Publications and source records attributed to Faure, A..

8 recordsLinked to original sources

bioRxiv2026

Questioning the G2 phase in the budding yeast cell cycle with a qualitative and possibilistic model

The budding yeast S. cerevisiae, a foundational model for cell cycle studies, exhibits a complex phase organisation (G1, S, G2/M) governed by checkpoints ensuring faithful cellular inheritance. However, the existence of a distinct G2 phase in yeast remains debated, with some advocating for a prometaphase instead. To address this issue, we developed a discrete-event, qualitative, and possibilistic model, the first one to our knowledge, to integrate organelle-level components (replication forks, sister chromatids, mitotic spindle, bud) while remaining parsimonious. Unlike molecular-centred or overly complex whole-cell models, this approach bridges broad systemic and finer mechanistic scales. Our results demonstrate that the model faithfully recapitulates cell cycle progression and supports the dispensable G2 phase. This possibilistic model inspired from recent applications in ecology advocates in favor of the necessity of prometaphase. This study thus provides a unifying and flexible framework to resolve long-standing ambiguities in yeast cell dynamics, while avoiding the pitfalls of excessive complexity or reductionism.

systems biology↗

bioRxiv2025

Adolescent social profiles predict adult social behaviour, monoamine brain content and regional gene expression

The study of inter-individual variability in animal behaviors during cognitive processes is crucial to better grasp the emergence of personality traits in healthy animals. Social experiences occurring at adolescence can affect the expression of the behavioural variability as it is a critical period of brain and cognitive plasticity. Here, we asked how individual variability of social profiles is shaped at adolescence and whether the profiles are associated with regional brain metabolites and gene expressions in the adult brain. At adolescence we determined a dominant profile expressing more dominance, a submissive profile expressing more submission and an explorer profile showing more novelty exploration than social interaction. Adolescent social behaviors are conserved at adulthood. Our data suggest that dominance tendencies already present at adolescence are likely to stabilize throughout life, thus shaping future social behaviors. Our results show that social profiles are not related to sex and life environment. However, being more dominant, interactive and socially motivated shape dopaminergic olfactory activity at adolescence. Also, showing the explorer or submissive profiles is associated with an opposite serotonin pattern in the cerebellum, but a similar kynurenine pattern in the prefrontal cortex and cerebellum, thus pointing toward major neurotransmitter systems in key regions for brain health. This work opens new perspectives on the importance of studying social profiles early in life and the individual neurobiological associated features that could potentially predict individual vulnerability. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/684125v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@bc26b7org.highwire.dtl.DTLVardef@91dba2org.highwire.dtl.DTLVardef@1ea7755org.highwire.dtl.DTLVardef@4083f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Allosteric and Energetic Remodeling by Protein Domain Extensions

Many functions of proteins are performed by independently folding structural units called domains. The structures of domains are conserved during evolution but they are not identical. For example, the >270 human PDZ domains vary in the number of secondary structure elements and in the length of loops. An important but largely unexplored question is the impact of these extensions on protein energy landscapes: beyond any immediate functional effects, do extensions also alter the consequences of perturbations elsewhere in the domain, altering the potential for regulation and evolvability? Here we perform massively parallel energetic measurements on a model human PDZ domain to directly and comprehensively answer this question. In total we quantify the binding to a ligand and abundance of [~]190,000 protein variants to quantify free energy changes for mutations throughout the canonical domain fold and [~]7,000 energetic couplings between these mutations and the two domain extensions, both alone and in combination. We find that both extensions--one structured and one more dynamic--substantially and specifically re-shape the energy landscape of the domain, with the removal of an [a]-helix altering the energetic consequences of 424 mutations in 54 sites on fold stability and 420 mutations in 56 sites on binding to a ligand. These changes to the energy landscape alter the effects of 330 allosteric mutations, including at solvent-accessible surface sites. Extending or pruning the domain therefore reshapes its energetic and allosteric landscape, adding and removing opportunities for the allosteric control of protein function.

biophysics↗

bioRxiv2025

Staphylococcal Internalization into Osteoblasts: A Partially Conserved Mechanism Across the Genus

Staphylococcus aureus, considered as a major human pathogen, is associated with severe infections such as bacteremia, endocarditis, skin and soft tissue infections, and bone and joint infections. Virulence mechanisms, such as biofilm formation and invasion/internalization of/into host cells, support the pathogenicity of S. aureus as they enable it to evade from the immune system and most antibiotic treatments. S. aureus can be internalized into non-professional phagocytic cells like fibroblasts, epithelial cells, endothelial cells and osteoblasts. The main pathway of internalization of S. aureus is FnBP-fibronectin-5{beta}1 integrin dependent. Interestingly, S. pseudintermedius, S. delphini and S. argenteus are able to invade osteoblasts, depending on the presence of FnBP-like proteins such as Staphylococcus pseudintermedius surface proteins D and L (SpsD/L) or Staphylococcus delphini surface protein Y (SdsY). However, the internalization capacity and mechanism have been poorly investigated in other staphylococci species. Here, we investigated the internalization capacity of staphylococci into osteoblasts at the genus level and attempted to correlate it with the presence of FnBP-like proteins by combining fibronectin adhesion assays, infection of osteoblasts and genome analysis. Over the 53 Staphylococcus species tested, half of them exhibited high internalization into osteoblasts. We highlighted that the "FnBP-fibronectin-5{beta}1 integrin" dependent internalization pathway of S. aureus, is well-conserved in 27 Staphylococcus species. In silico analysis identified multiple FnBP-like proteins correlating with the highly internalized species and showing diversity in their sequence organization, likely due to multiple acquisitions of such encoding genes throughout Staphylococcus evolution. AUTHOR SUMMARYStaphylococcus aureus is a pathogenic bacterium that causes severe infections including bone and joint infections. It invades bone cells, such as osteoblasts, using the bacterial surface protein FnBP, which binds to fibronectin, an extracellular compound, which subsequently binds to 5{beta}1 integrin on the surface of osteoblasts. This cross-linking enables active internalization of S. aureus by the cells and potential intracellular persistence, which are responsible for the ability to induce staphylococcal chronic infections. While four species have been studied for their internalization into osteoblasts, a comprehensive genus-level investigation remains unexplored. Therefore, we investigated the conservation of this internalization capacity among the genus Staphylococcus, including a significant number of species of animal origin. Approximately half of the genus is capable of invading osteoblasts at varying levels via 5{beta}1 integrin. Additionally, homologous proteins to FnBP were identified in most highly internalized species, suggesting a similar pathway of cell internalization to that of S. aureus. Genomic analysis reveals these proteins were acquired multiple times during evolution, suggesting they provide an advantage for host infection. In the context of One Health approach and the increasing number of animal pathogens causing human infections, understanding staphylococcal pathogenicity will help anticipate the emergence of new infectious diseases.

microbiology↗

bioRxiv2024

The allosteric landscape of the Src kinase

Enzymes catalyze the reactions of life and are the targets of most small molecule drugs. Most drugs target conserved enzyme active sites, often causing problems of specificity and toxicity. Targeting allosteric sites can increase specificity, overcome resistance mutations, and allow fine-tuning of activity. However, most enzymes have no known allosteric sites and methods do not exist to comprehensively identify them. Here we present a general and fast approach to chart allosteric communication in enzymes and apply it to the Src kinase to produce the first comprehensive map of negative and positive allosteric control of an enzymatic activity. Allostery in the Src kinase domain is pervasive, anisotropic, partially predictable, and modulated by regulatory domains. Multiple surface pockets of Src are allosterically active and so genetically-prioritized for the development of inhibitory and activating drugs. Using this approach it should be possible to chart global allosteric maps of many kinases and other enzymes important for medicine and biotechnology. HighlightsO_LIFirst comprehensive map of negative and positive allosteric control of an enzymatic activity, the Src kinase. C_LIO_LIAllosteric communication is pervasive, distance dependent, and anisotropic. C_LIO_LIAllostery is conserved and modulated in the presence of the Src regulatory domains. C_LIO_LIGenetic prioritization of druggable surface pockets for Src inhibition and activation. C_LIO_LIAllosteric maps can now be constructed for many medically and industrially important kinases and enzymes. C_LI

biophysics↗

bioRxiv2024

Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing

Altered splicing is a frequent mechanism by which genetic variants cause disease and antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for multiple pathologies including patient-customized treatments for rare diseases. However, the regulatory architecture of human exons remains poorly understood and AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that that systematic deletion scans -which can be made experimentally at very low cost - provide an efficient strategy to chart the regulatory landscape of human exons and to rapidly identify effective splicing-modulating oligonucleotides in a fully quantitative manner. Our results suggest a mechanism for the evolutionary origins of unusually short microexons and the repression of transmembrane domain-encoding exons, and reveal a checkerboard architecture of sequential enhancers and silencers in a model alternative exon. Accurate prediction of the effects of deletions using deep learning provides a resource, DANGO, that maps the splicing regulatory landscape of all human exons and predicts effective splicing-altering antisense oligonucleotides genome-wide.

genetics↗

bioRxiv2023

The genetic architecture of protein interaction affinity and specificity

Proteins function in crowded cellular environments in which they must bind to specific target proteins but also avoid binding to many other off-target proteins. In large protein families this task is particularly challenging because many off-target proteins have very similar structures. How this specificity of physical protein-protein interactions in cellular networks is encoded and evolves is not very well understood. Here we address the question of specificity-encoding by comprehensively quantifying the effects of all mutations in one protein, JUN, on its binding to all other members of a protein family, the 54 human basic leucine zipper transcription factors. Fitting a global thermodynamic model to the data reveals that most affinity changing mutations equally affect JUNs propensity to bind to all its interaction partners. Mutations that alter the specificity of binding are much rarer. These specificity-altering mutations are, however, distributed throughout the JUN interaction interface. JUNs interaction specificity is encoded by both positive determinants that promote on-target interactions and negative determinants that prevent off-target interactions. Indeed, about half of the specificity-defining residues in JUN have dual functions and both promote on-target binding and prevent off-target binding. Whereas nearly all mutations that alter specificity are pleiotropic and also alter the affinity of binding to all interaction partners, the converse is not true with mutations outside of the interface able to tune affinity without affecting specificity. Our results provide the first global view of how mutations in a protein affect binding to all its potential interaction partners and reveal the distributed encoding of specificity and affinity in an interaction interface. They also show how the modular architecture of coiled-coils provides an elegant solution to the challenge of optimising specificity and affinity in a large protein family.

systems biology↗

bioRxiv2020

The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations

Amyloid fibrils are associated with many human diseases but how mutations alter the propensity of proteins to form fibrils has not been comprehensively investigated and is not well understood. Alzheimers Disease (AD) is the most common form of dementia with amyloid plaques of the amyloid beta (A{beta}) peptide a pathological hallmark of the disease. Mutations in A{beta} also cause familial forms of AD (fAD). Here we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of A{beta}. The resulting genetic landscape reveals fundamental mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the in vivo nucleation scores accurately identify all known dominant fAD mutations, validating this simple cell-based assay as highly relevant to the human genetic disease and suggesting accelerated fibril nucleation is the ultimate cause of fAD. Our results provide the first comprehensive map of how mutations alter the formation of any amyloid fibril and a validated resource for the interpretation of genetic variation in A{beta}. HighlightsO_LIFirst comprehensive map of how mutations alter the propensity of a protein to form amyloid fibrils. C_LIO_LICharge and gatekeeper residues in the disordered N-terminus of amyloid beta prevent fibril nucleation. C_LIO_LIRates of nucleation in a cell-based assay accurately identify the mutations that cause dominant familial Alzheimers disease. C_LIO_LIThe combination of deep mutational scanning and human genetics provides a general strategy to quantify the disease-relevance of in vitro and in vivo assays. C_LI

genomics↗