Biology subjects

Deville, C.

Publications and source records attributed to Deville, C..

4 recordsLinked to original sources

bioRxiv2026

A hotspot for conformational heterogeneity driven by proline isomerisation in the androgen receptor disordered N-terminal domain

The androgen receptor is a hormone-dependent transcription factor that regulates a wide range of physiological processes and plays a pivotal role in the development of prostate cancer. Its 555-residue, intrinsically disordered, N-terminal domain is involved in the modulation of transcriptional activity by recruiting co-regulators and mediating the formation of biomolecular condensates. This study reports on the characterisation of a conserved domain located in the C-terminal region of the androgen receptor N-terminal domain, at atomic level, using nuclear magnetic resonance spectroscopy. This proline rich region exhibits extensive conformational heterogeneity driven by highly populated cis proline conformers that are stabilised through interactions with adjacent aromatic residues. We demonstrate that the cis-proline population is modulated by phosphorylation as well as cancer-associated mutations. This suggests that proline driven conformational heterogeneity at the C-terminal region of androgen receptor N-terminal domain is involved in the regulatory function of this transcription factor.

biophysics↗

bioRxiv2026

Proton FLASH preserves neurocognition across delivery techniques: implications for clinical translation in pediatric brain tumors

BackgroundRadiation therapy is integral to the curative treatment of childhood brain tumors but contributes to late neurocognitive impairment in survivors. FLASH (ultra-high dose rate, >40Gy/s) reduces normal-tissue toxicity in preclinical models, and proton-FLASH is currently the only modality capable of delivering ultra-high dose rates to the deep targets, such as pediatric brain tumors. However, two questions remain unresolved before clinical translation: (1) whether the FLASH effect can be achieved on synchrotron-based proton systems, which deliver protons in discrete spills that may be insufficient to cover a clinical target within a single delivery, and (2) which dose-rate metric, among the multiple definitions currently used in the field, best predicts the biological FLASH effect. MethodsC57BL/6 mice (7-8 weeks) received 10 Gy whole-brain RT via a clinical Hitachi ProBEAT synchrotron with CBCT-guided delivery, using three transmission-beam techniques: single-spill pencil beam scanning (SS PBS), multi-spill PBS with [~]2-second inter-spot delay (MS PBS), and passive scatter (PS), compared to conventional (CONV) delivery and unirradiated controls (n=24-28/group, equal sex distribution). Dose rate was quantified using three frameworks: field dose rate (FDR), PBS dose rate (PBSDR), and dose-averaged dose rate (DADR). Recognition memory was assessed by novel object recognition (NOR) at 6 weeks post-RT, and cognitive flexibility was assessed via touchscreen visual discrimination and reversal learning at 14 weeks. Hippocampal neuroinflammation was evaluated by immunofluorescence and immunohistochemistry for Iba1, NeuN, and GFAP. ResultsFLASH conditions were met by SS PBS and PS under all three dose-rate definitions, but MS PBS qualified as FLASH only by DADR. Despite this, neuroprotection was preserved across all three FLASH techniques: discrimination index was significantly higher for SS PBS (P=0.021), MS PBS (P=0.008), and PS (P<0.001) versus CONV, with no significant difference between FLASH techniques. On touchscreen testing, FLASH-treated females demonstrated preserved cognitive flexibility (P=0.047 vs. CONV on reversal learning correct trials). Iba1+ microglia were reduced in FLASH compared to CONV mice, with morphology suggestive of preserved homeostatic state. ConclusionsSynchrotron-based proton FLASH preserves neurocognitive function across all delivery techniques, including under multi-spill delivery essential for treating clinical-scale pediatric brain tumors. Critically, this neuroprotection was observed even for deliveries that qualified as FLASH only by DADR, identifying DADR as the dose-rate metric most relevant to the biological FLASH effect with direct implications for clinical trial design and dose-rate reporting standards.

cancer biology↗

bioRxiv2022

In vitro characterization of the full-length human dynein-1 cargo adaptor BicD2

Cargo adaptors are crucial in coupling motor proteins with their respective cargos and regulatory proteins. BicD2 is a prominent example within the cargo adaptor family. BicD2 is able to recruit the microtubule motor dynein to RNA, viral particles and nuclei. The BicD2-mediated interaction between the nucleus and dynein is implicated in mitosis, interkinetic nuclear migration (INM) in radial glial progenitor cells, and neuron precursor migration during embryonic neocortex development. In vitro studies involving full-length cargo adaptors are difficult to perform due to the hydrophobic character, low-expression levels, and intrinsic flexibility of cargo adaptors. Here we report the recombinant production of full-length human BicD2 and confirm its biochemical activity by interaction studies with RanBP2. We also describe pH-dependent conformational changes of BicD2 using cryoEM, template-free structure predictions, and biophysical tools. Our results will help define the biochemical parameters for the in vitro reconstitution of higher order BicD2 protein complexes.

biochemistry↗

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↗