Biology subjects

Demange, P.

Publications and source records attributed to Demange, P..

6 recordsLinked to original sources

bioRxiv2024

Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

Macrophage inducible Ca2+-dependent lectin (Mincle) receptor recognizes Mycobacterium tuberculosis glycolipids to trigger an immune response. This host membrane receptor is thus a key player in the modulation of the immune response to infection by M. tuberculosis, and has emerged as a promising target for the development of new vaccines for tuberculosis. The recent development of the Martini 3 force field for coarse-grained (CG) molecular modeling allow the study of interactions of soluble proteins with small ligands but its use for the study of interactions with lipids remains less explored. Here, we present a refined approach detailing a protocol for modeling such interactions at a CG level using the Martini 3 force field. Using this approach, we studied Mincle and identified critical parameters governing ligand recognition, such as loop flexibility and the regulation of hydrophobic groove formation by calcium ions. In addition, we assessed ligand affinity using free energy perturbation calculations. Our results offer mechanistic insight into the interactions between Mincle and glycolipids, providing a basis for rational design of molecules targeting this type of membrane receptors.

bioinformatics↗

bioRxiv2024

The human and mouse dendritic cell receptor DCIR binds to LRP1 N-glycans containing terminal galactoses, including the α-Gal antigen

The dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed by myeloid cells that plays a key immunoregulatory role in a wide range of diseases, from inflammation to cancer. However, the ligand(s) of DCIR remain(s) unknown, hampering our understanding of the exact function of this immune receptor. Here, we found that both human DCIR and mouse DCIR1 bind specifically to the low-density lipoprotein receptor-related protein 1 (LRP1), a heavily glycosylated receptor mediating the clearance of various molecules from the extracellular matrix and apoptotic cells. This interaction is mediated by galactose-terminated biantennary complex-type N-glycans, including those carrying the immunogenic -Gal epitope. Our study provides a deeper understanding of the role of DCIR in immune regulation and its potential impact on a range of immune disorders, highlighting its specificity in ligand recognition which is crucial for developing therapeutic strategies.

immunology↗

bioRxiv2021

Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms

Transition metals are toxic at high concentrations. The P1B-ATPase metal exporter CtpC/Rv3270 is required for resistance to zinc poisoning in the human pathogen Mycobacterium tuberculosis. Here, we discovered that zinc resistance also depends on the chaperone-like protein PacL1/Rv3269. PacL1 bound Zn2+, but unlike PacL1 and CtpC, the PacL1 metal-binding motif (MBM) was required only at high zinc concentrations. PacL1 co-localized with CtpC in dynamic microdomains within the mycobacterial plasma membrane. Microdomain formation did not require flotillins nor the PacL1 MBM. Instead, loss of the PacL1 Glutamine/Alanine repeats led to loss of CtpC and sensitivity to zinc. PacL1 and CtpC are within the same operon, and homologous PacL1-P1B-ATPase pairs are widely distributed within and across prokaryotes. PacL1 colocalized and functioned redundantly with PacL orthologs in Mycobacterium tuberculosis. Overall, our study suggests that PacL proteins are scaffolds that assemble P-ATPase-containing metal efflux platforms, a novel type of functional membrane microdomain that underlies bacterial resistance to metal poisoning.

microbiology↗

bioRxiv2021

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/460423v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@12daae1org.highwire.dtl.DTLVardef@12db406org.highwire.dtl.DTLVardef@1863517org.highwire.dtl.DTLVardef@7b548_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

biochemistry↗

bioRxiv2020

Defining the function of OmpA in the Rcs stress response

OmpA, a protein commonly found in the outer membrane of Gram-negative bacteria, has served as a paradigm for the study of {beta}-barrel proteins for several decades. In Escherichia coli, OmpA was previously reported to form complexes with RcsF, a surface-exposed lipoprotein that triggers the Rcs stress response when damage occurs in the outer membrane and the peptidoglycan. How OmpA interacts with RcsF and whether this interaction allows RcsF to reach the surface has remained unclear. Here, we integrated in vivo and in vitro approaches to establish that RcsF interacts with the C-terminal, periplasmic domain of OmpA, not with the N-terminal {beta}-barrel, thus implying that RcsF does not reach the bacterial surface via OmpA. Our results reveal a novel function for OmpA in the cell envelope: OmpA competes with the inner membrane protein IgaA, the downstream Rcs component, for RcsF binding across the periplasm, thereby regulating the Rcs response.

microbiology↗

bioRxiv2018

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: a Mendelian randomization study

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to the developmental environment. In environments characterized by harsh conditions, adopting a fast life history strategy may increase fitness. In line with this, there is evidence demonstrating that greater childhood adversity is associated with earlier age at menarche. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114883-181,255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.0001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and results should be treated with caution. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.

evolutionary biology↗