Biology subjects

Lescop, E.

Publications and source records attributed to Lescop, E..

5 recordsLinked to original sources

bioRxiv2026

Cytoplasmic FKBP7 reflux controls NFE2L1 levels as an adaptive response to chemotherapy in prostate cancer cells

Understanding how cancer cells adapt to chemotherapy is essential for overcoming resistance. One mechanism involved in taxane resistance in prostate cancer is mediated by FKBP7, a still-understudied endoplasmic reticulum-resident cis-trans isomerase. Using cell fractionation, we demonstrate that the ERAD-independent retrotranslocation of FKBP7 into the cytosol correlates with the oxidative stress triggered by chemotherapy, as an escape response. Once in the cytosol, FKBP7 interacts with the translation machinery and with eIF4G1, specifically with its C-terminal HEAT3 domain. Following FKBP7 silencing, polysome profiling and RNA sequencing identified the transcription factor NFE2L1 - a key regulator of oxidative stress adaptation - as an effector of FKBP7. Here, we also produced the first NMR spectra of the FKBP7 catalytic domain, revealing a well-folded protein that binds to rapamycin and everolimus but not to FK506. Overall, our results demonstrate that chemotherapy-induced oxidative stress triggers an adaptive mechanism in which FKBP7 is translocated into the cytosol where it modulates NFE2L1, thereby enabling the survival of resistant cells. These findings lead us to propose the targeting of FKBP7/NFE2L1 signaling as a strategy to overcome adaptive resistance.

cancer biology↗

bioRxiv2025

Atomic scale description of the allosteric coupling between a lipid bilayer and a membrane protein

Biological membranes are complex environments whose functions are closely tied to the dynamic interactions between lipids and proteins. Here, we utilize high-pressure NMR of lipid nanodiscs paired with molecular dynamics simulations to elucidate at the atomic scale the allosteric dialog between the lipid bilayer and a bacterial model membrane protein, OmpX. We discover that OmpX delays the gelation process by liquefying the annular shell of lipids through hydrophobic and roughness matching processes at the protein surface. Furthermore, the alteration of the mechanical properties of the lipid bilayer directly impacts the energy landscape of amino acid side chains at the lipid/protein interface, but also, unexpectedly, at the protein core. Our work highlights a potential thermodynamically coupled but kinetically uncoupled allosteric pathway linking lipid dynamics with the interior of membrane proteins, directly impacting our understanding of membrane function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/634742v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@5c02ddorg.highwire.dtl.DTLVardef@c033c5org.highwire.dtl.DTLVardef@86f90forg.highwire.dtl.DTLVardef@149480e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Structural transitions in TCTP tumor protein upon Mcl-1 binding

SummaryTranslationally Controlled Tumour Protein (TCTP) is a pro-survival factor in tumor cells. TCTP inhibits the mitochondrial apoptosis pathway by potentiating the anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-xL. Specifically, TCTP binds Bcl-xL and inhibits the Bax-dependent Bcl-xL-induced cytochrome c release and TCTP reduces Mcl-1 turnover by inhibiting its ubiquitinylation, thus resulting in decreased Mcl-1 mediated apoptosis. TCTP owns a BH3-like motif forming a {beta}-strand buried in the globular domain of the protein. The crystal structure of TCTP BH3-like peptide in complex with Bcl-xL highlighted the -helical conformation of TCTP BH3-like motif, suggesting major changes in TCTP structure upon complex formation. However, the structural impact of the interaction on the full-length TCTP and the structural description of TCTP/Mcl-1 interaction are still lacking. Here using biophysical/biochemical methods (NMR, SAXS, circular dichroism, limited proteolysis), we provide an in-depth description of the TCTP/Mcl-1 complex. We demonstrate that full length TCTP binds to the BH3 binding groove of Mcl-1 via its BH3-like motif which interconverts between different binding modes at the micro- to milli-second timescale. As a consequence of the engagement of the BH3-like motif in the interface, the TCTP globular domain is destabilized into a molten-globule state. We also establish that the residue D16 in TCTP BH3-like motif is crucial for the stability and dynamics of the intermolecular interface. As a conclusion, we reveal here in details the structural plasticity of TCTP and discuss its implications for TCTP biology and for future anticancer drug design strategies aiming at targeting TCTP complexes. ContactEwen Lescop, ewen.lescop@cnrs.fr. Supplementary InformationSupplementary figures, tables and files.

biochemistry↗

bioRxiv2021

EpyNN: Educational python for Neural Networks

SummaryArtificial Neural Networks (ANNs) have achieved unequaled performance for numerous problems in many areas of Science, Business, Public Policy, and more. While experts are familiar with performance-oriented software and underlying theory, ANNs are difficult to comprehend for non-experts because it requires skills in programming, background in mathematics and knowledge of terminology and concepts. In this work, we release EpyNN, an educational python resource meant for a public willing to understand key concepts and practical implementation of scalable ANN architectures from concise, homogeneous and idiomatic source code. EpyNN contains an educational Application Programming Interface (API), educational workflows from data preparation to ANN training and a documentation website setting side-by-side code, mathematics, graphical representation and text to facilitate learning and provide teaching material. Overall, EpyNN provides basics for python-fluent individuals who wish to learn, teach or develop from scratch. AvailabilityEpyNN documentation is available at https://epynn.net and repository can be retrieved from https://github.com/synthaze/epynn. ContactStephanie Olivier-Van-Stichelen, solivier@mcw.edu. Supplementary InformationSupplementary files and listings.

scientific communication and education↗

bioRxiv2020

Structural and dynamic characterization of the C-terminal tail of ErbB2: disordered but not random

ErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poor prognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in the last twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding of the receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains very poorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction is triggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the first description of ErbB2 disordered tail at atomic resolution, using NMR and SAXS. We show that although no part of CtErbB2 has any stable secondary or tertiary structure, it has around 20% propensity for a N-terminal helix that is suspected to interact with the kinase domain, and many PPII stretches distributed all along the sequence, forming potential SH3 and WW domains binding sites. Moreover, we identified a long-range transient contact involving CtErbB2 termini. These characteristics suggest new potential mechanisms of auto-regulation and protein-protein interaction. SIGNIFICANCEWe report here the first description of the receptor tyrosine kinase ErbB2 disordered tail (CtErbB2) at atomic resolution, using NMR and SAXS. We show that although CtErbB2 exhibits no stable structure, it does exhibit partial secondary and tertiary structures likely important for its function. These structural elements are consistent with an active role of the C-terminal tail in the regulation of the receptors activity, thanks to the presence of preformed structures for intramolecular interactions, as well as long-range contacts modulating accessibility of those sites and proline interaction sites distinct from the main tyrosine sites. Together, those results reinforce the view that disordered tails of receptors are more than random anchors for partners.

biophysics↗