Biology subjects

Haanappel, E.

Publications and source records attributed to Haanappel, E..

4 recordsLinked to original sources

bioRxiv2025

Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration

Cortical migration is a complex process in which neurons migrate along radial glial cells (RGC) to form functional layers. Teneurins (Ten1-4) play a role by interacting with Latrophilins (Lphn/ADGRL1-3). Teneurins are also known as cell adhesion molecules, but how homophilic and heterophilic Teneurin interactions are integrated is unknown. Here, single-particle-cryo-EM data of Ten2 shows that canonical Latrophilin-binding is sterically incompatible with Ten2-dimerisation, making these interactions exclusive. We engineered surface mutations that specifically disrupt Ten2-Ten2 or Ten2-Latrophilin interactions. These are transferrable to Ten4, suggesting conserved binding mechanisms. Proteomics, in-vivo-gene-editing and super-resolution-microscopy show that Ten4 is expressed along RGC fibres and that migrating neurons switch from low-to-high Ten4-expression. Ten4 expression is highest in the cortical plate where Ten4-Ten4 interactions reduce RGC-attachment. In the intermediate zone, Ten4-Latrophilin interactions are required to promote neuron-RGC association. The results show how Ten4 orchestrates cortical migration by exclusive structural mechanisms, underpinning the integration of distinct migration programmes. Note: the adhesion GPCR ADGRL is largely referred to as Latrophilin, which is in line with previous papers in the Teneurin field. We would be happy to implement a different naming scheme if recommended.

neuroscience↗

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↗

bioRxiv2020

Phthiocerol dimycocerosates from Mycobacterium tuberculosis increase the membrane activity of bacterial effectors and host receptors

Mycobacterium tuberculosis (Mtb) synthesizes a variety of atypical lipids that are exposed at the cell surface and help the bacterium infect macrophages and escape elimination by the cells immune responses. In the present study, we investigate the mechanism of action of one family of hydrophobic lipids, the phthiocerol dimycocerosates (DIM/PDIM), major lipid virulence factors. DIM are transferred from the envelope of Mtb to host membranes during infection. Using the polarity-sensitive fluorophore C-Laurdan, we visualized that DIM increase the membrane polarity of a supported lipid bilayer put in contact with mycobacteria, even beyond the site of contact. We observed that DIM activate the complement receptor 3, a predominant receptor for phagocytosis of Mtb by macrophages. DIM also increased the activity of membrane-permeabilizing effectors of Mtb, among which the virulence factor EsxA. This is consistent with previous observations that DIM help Mtb disrupt host cell membranes. Taken together, our data show that transferred DIM spread within the target membrane, remodel lipid organization and increase the activity of host cell receptors and bacterial effectors, diverting in a nonspecific manner host cell functions. We therefore bring new insight into the molecular mechanisms by which DIM increase Mtbs capability to escape the cells immune responses.

microbiology↗

bioRxiv2019

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen Mycobacterium tuberculosis (Mtb). While this lipid promotes the entry of Mtb into macrophages, which occurs via phagocytosis, its molecular mechanism of action is unknown. Here, we combined biophysical, cell biology, and modelling approaches to reveal the molecular mechanism of DIM action on macrophage membranes leading to the first step of Mtb infection. MALDI-TOF mass spectrometry showed that DIM molecules are transferred from the Mtb envelope to macrophage membranes during infection. Multi-scale molecular modeling and 31P-NMR experiments revealed that DIM adopts a conical shape in membranes and aggregate in the stalks formed between two opposing lipid bilayers. Infection of macrophages pre-treated with lipids of various shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken together, these results reveal how the molecular shape of a mycobacterial lipid can modulate the biological function of macrophages.

biophysics↗