Biology subjects

Van der Giessen, E.

Publications and source records attributed to Van der Giessen, E..

4 recordsLinked to original sources

bioRxiv2025

A coarse-grained MD model for disorder-to-order transitions in polyQ aggregation

Polyglutamine (polyQ) aggregation plays a central role in several neurodegenerative diseases, including Huntingtons disease. To investigate the underlying mechanisms of polyQ aggregation, we developed a coarse-grained molecular dynamics model calibrated using atomistic simulations and experimental data. To assess the models predictive power beyond the calibrated parameter set, we systematically varied side chain hydrophobicity and hydrogen bonding strength to explore a broader range of aggregation pathways. These pathways ranged from nucleated growth to liquid-to-solid phase transitions. Through seeded aggregation simulations, we observed that amyloid growth occurs primarily in the {beta}-sheet elongation direction, although growth through steric zippering was also observed. Longer polyQ sequences (Q48) exhibited significantly faster growth compared to shorter sequences (Q23), underscoring the role of chain length in aggregation kinetics. Our model provides a versatile framework for studying polyQ aggregation and offers a foundation for investigating broader aggregation mechanisms and sequence variations.

biophysics↗

bioRxiv2024

Nuclear transport at full amino-acid resolution

Recent studies of nuclear pore complexes (NPCs) have provided detailed descriptions of the core scaffold structures, yet fall short in resolving the dynamic FG-meshwork with similar precision. Here, we present a novel modeling framework that enables the simulation of nuclear transport at full amino-acid resolution. We describe the distributions of the different FG-Nups in the central transporter and highlight the dynamic nature of the FG-meshwork, with FG-FG interaction lifetimes on the order of nanoseconds. Our findings reveal that Nsp1, the most abundant FG-Nup in the NPC, creates a central meshwork due to its unique bimodal structure, that is essential for controlling both passive and active transport. By adding nuclear transport receptors (NTRs)--specifically Kap95--to the pore, we demonstrate that NTRs play a key role in increasing the energy barrier for translocation of inert particles. The NTRs are subject to a dynamic interplay between binding to FG motifs and the temporal fluctuations of the FG-meshwork, leading to transient voids through which they move. Overall, our simulations identify a dense GLFG-ring coated by lower-mobility Kaps and a central dynamic FG-FG meshwork to create a reduced-dimensional transport surface of optimal binding avidity that drives Kap translocation.

biophysics↗

bioRxiv2023

C9orf72 polyPR directly binds to various nuclear transport components

The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kap{beta} family of nuclear transport receptors. Beside Kap{beta}s, several other types of transport components have been linked to NCT impairments in R-DPRs expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino-acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Imp family, CAS (the specific exporter of Imp) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Imp, with cargo-NLS release from Imp, and with Imp export from the nucleus. The abundance of polyPR binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.

biophysics↗

bioRxiv2022

Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors

Nucleocytoplasmic transport (NCT) is affected in several neurodegenerative diseases including C9orf72-ALS. It has recently been found that arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72 repeat expansions, directly bind to several importins. To gain insight into how this can affect nucleocytoplasmic transport, we use coarse-grained molecular dynamics simulations to study the molecular interaction of poly-PR, the most toxic DPR, with several Kap{beta}s (importins and exportins). We show that poly-PR-Kap{beta} binding depends on the net charge per residue (NCPR) of the Kap{beta}, salt concentration of the solvent, and poly-PR length. Poly-PR makes contact with the inner surface of most importins, which strongly interferes with Kap{beta} binding to cargo-NLS, IBB, and RanGTP in a poly-PR length-dependent manner. Longer poly-PRs at higher concentrations are also able to make contact with the outer surface of importins that contain several binding sites to FG-Nups. We also show that poly-PR binds to exportins, especially at lower salt concentrations, interacting with several RanGTP and FG-Nup binding sites. Overall, our results suggest that poly-PR might cause length-dependent defects in cargo loading, cargo release, Kap{beta} transport and Ran gradient across the nuclear envelope.

biophysics↗