A5021040321- Protein Structure and Dynamics
- Advanced NMR Techniques and Applications
- Signaling Pathways in Disease
- Alzheimer's disease research and treatments
- NMR spectroscopy and applications
- Chemical Synthesis and Analysis
- Enzyme Structure and Function
- Metabolomics and Mass Spectrometry Studies
- Microtubule and mitosis dynamics
- Hepatitis C virus research
- Molecular spectroscopy and chirality
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Advanced MRI Techniques and Applications
- Toxin Mechanisms and Immunotoxins
- Biochemical and Structural Characterization
- Enzyme Production and Characterization
- Spectroscopy and Quantum Chemical Studies
- Biochemical and Molecular Research
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Electron Spin Resonance Studies
- Mass Spectrometry Techniques and Applications
- Prion Diseases and Protein Misfolding
Institut de Mathématiques de Toulouse
2025
Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
2019-2024
Centre National de la Recherche Scientifique
2014-2024
Université de Toulouse
2016-2024
Institut National des Sciences Appliquées de Toulouse
2016-2024
Biotechnology Institute
2019-2021
Unité de Glycobiologie Structurale et Fonctionnelle
2009-2020
Local Initiatives Support Corporation
2017-2019
Université de Lille
2009-2019
Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
2015-2019
Significance In Alzheimer’s disease, the microtubule-associated protein Tau is invariably found in a hyperphosphorylated and aggregated form. Whether (hyper)phosphorylation can drive aggregation less clear, no precise phosphorylation pattern leading to has been described. Combining vitro assays with purified kinases rat brain extract analytical power of NMR spectroscopy, we unravel here that drives its aggregation. The results point importance this posttranslational modification Tau's...
DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and vivo. It currently being evaluated phase II clinical trials. DEB025 binds to CypA, peptidyl-prolyl cis-trans isomerase which crucial cofactor for HCV replication. Here we report that it was very difficult select resistant replicons (genotype 1b) DEB025, requiring an average of 20 weeks (four independent experiments), compared the typically <2 protease or...
We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) hyperphosphorylated tau proteins, representative hallmark Alzheimer's disease (AD). The probe 1 incorporates BODIPY unit and two Zn(II)−2,2′-dipicolylamine (Dpa) complexes as binding site phosphorylated amino acid residues. Using fluorescence titration to evaluate sensing properties toward several peptide segments derived from protein, we found that binds preferentially peptides...
We report here a biochemical and structural characterization of domain 2 the nonstructural 5A protein (NS5A) from JFH1 Hepatitis C virus strain its interactions with cyclophilins A B (CypA CypB). Gel filtration chromatography, circular dichroism spectroscopy, finally NMR spectroscopy all indicate natively unfolded nature this NS5A-D2 domain. Because mutations in have been linked to cyclosporin resistance, we used investigate potential between cellular CypA CypB. observed direct molecular...
Abstract The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. emergence human TSLP as a clinical target against calls for maximally harnessing its therapeutic potential via structural mechanistic considerations. Here we employ an integrative experimental approach focusing on productive antagonized complexes free cytokine. We...
Phosphorylation of the microtubule-associated Tau protein plays a major role in regulation its activity tubulin polymerization and/or stabilization microtubule assembly. A dysregulation phosphorylation/dephosphorylation balance leading to hyperphosphorylation proteins neurons is thought favor their aggregation into insoluble filaments. This turn might underlie neuronal death as encountered many neurodegenerative disorders, including Alzheimer's disease. Another post-translational...
Abstract Prion‐like transcellular spreading of tau in Alzheimer's Disease (AD) is mediated by binding to cell surface heparan sulfate (HS). However, the structural determinants for tau–HS interaction are not well understood. Microarray and SPR assays structurally defined HS oligosaccharides show that a rare 3‐ O ‐sulfation (3‐ ‐S) significantly enhances binding. In Hs3st1 −/− (HS ‐sulfotransferase‐1 knockout) cells, reduced ‐S levels diminished both internalization tau. culture, addition...
The neuronal Tau protein is involved in stabilizing microtubules but also the major component of paired helical filaments (PHFs), intracellular aggregates that characterize Alzheimer's disease (AD) neurons. In vitro, can be induced to form AD-like by adding polyanions such as heparin. While previous studies have identified microtubule binding repeats (MTBRs) player aggregation, fact full-length does not aggregate itself indicates presence inhibitory factors. Charge and conformational changes...
The phosphorylation of the neuronal Tau protein modulates both its physiological role microtubule binding and aggregation into paired helical fragments observed in Alzheimer's diseased neurons. However, detailed knowledge at specific sites has been hampered by analytical difficulties to evaluate level site-specific phosphate incorporation. Even with recombinant kinases, mass spectrometry immunodetection are not evident for determining full pattern a qualitative quantitative manner. We show...
Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions one such holoenzyme in vivo, we generated mice lacking PR61/B’δ (B56δ), a subunit highly expressed neural tissues. In PR61/B’δ-null microtubule-associated tau becomes progressively phosphorylated at pathological epitopes restricted brain areas, marked immunoreactivity for misfolded MC1-conformation but without neurofibrillary tangle...
Nonstructural protein 5A (NS5A) is essential for hepatitis C virus (HCV) replication and constitutes an attractive target antiviral drug development. Although structural data its in-plane membrane anchor domain D1 are available, the structure of domains 2 (D2) 3 (D3) remain poorly defined. We report here a comparative molecular characterization NS5A-D3 HCV JFH-1 (genotype 2a) Con1 1b) strains. Combining gel filtration, CD, NMR spectroscopy analyses, we show that natively unfolded. However,...
The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice pharmacological inhibition O-GlcNAc-ase. Chronic treatment ageing mitigated their loss in body-weight improved motor deficits, while the survival 3-fold higher at pre-fixed study endpoint age 9.5 months. Moreover, O-GlcNAc-ase significantly breathing parameters mice,...
Abstract Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout genetic studies have linked IDE to Alzheimer’s disease type-2 diabetes. As the major insulin-degrading protease, candidate drug target in Here we used kinetic target-guided synthesis design first catalytic site inhibitor of suitable for vivo (BDM44768). Crystallographic small angle X-ray scattering analyses show it locks closed conformation. Among panel...
Phosphorylation of the neuronal Tau protein is implicated in both regulation its physiological function microtubule stabilization and pathological propensity to aggregate into fibers that characterize Alzheimer's diseased neurons. However, how specific phosphorylation events influence aspects biology remains largely unknown. In this study, we address structural impact by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment (Tau[Ser208-Ser324] = TauF4). TauF4 was...
Lysine acetylation of the neuronal Tau protein was described as a novel mechanism posttranslational regulation functions with important outcomes in microtubule binding and aggregation processes related to Alzheimer's disease. Here, we unravel at per-residue resolution pattern full-length by Creb-binding (CBP) acetyltransferase using high-resolution nuclear magnetic resonance spectroscopy. Our study gives quantitative overview CBP-mediated examines catalytic proficiency because nonenzymatic...
The capacity of endogenous Tau to bind DNA has been recently identified in neurons under physiological or oxidative stress conditions. Characterization the protein domains involved Tau-DNA complex formation is an essential first step clarifying contribution interactions neurological biological processes. To identify amino acid residues interaction with oligonucleotides, we have characterized a using nuclear magnetic resonance spectroscopy. Interaction AT-rich GC-rich 22 bp oligonucleotide...
The application of high-throughput genomic approaches has revealed 24 novel risk loci for Alzheimer's disease (AD). We recently reported that the bridging integrator 1 (BIN1) gene is linked to Tau pathology. used glutathione S-transferase pull-down assays and nuclear magnetic resonance (NMR) experiments demonstrate BIN1 proteins interact directly then map interaction between BIN1's SH3 domain Tau's proline-rich (PRD) . Our NMR data showed phosphorylation at Thr231 weakens SH3-PRD...
A general approach for the efficient hydrogen-isotope exchange of nucleobase derivatives is described. Catalyzed by ruthenium nanoparticles, using mild reaction conditions, and involving either D2 or T2 as isotopic sources, this possesses a wide substrate scope high solvent tolerability. This novel method facilitates access to essential diagnostic tools in drug discovery development: tritiated pharmaceuticals with specific activities deuterated oligonucleotides suitable use internal...