Biology subjects

Dekker, M.

Publications and source records attributed to Dekker, M..

6 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↗

bioRxiv2025

Disruption of ADNP-KDM1A-GTF2I complex drives neural differentiation imbalance in Helsmoortel-Van der Aa syndrome

Mutations in ADNP (Activity-Dependent Neuroprotective Protein) are among the most frequent monogenic causes of autism spectrum disorder (ASD) and lead to Helsmoortel-Van der Aa syndrome (HVDAS). Yet how ADNP dysfunction leads to HVDAS is unclear. We employed patient-derived induced pluripotent stem cells, cortical organoids and ADNP KO human neural stem cells (hNSCs) to clarify the cellular and molecular mechanism of HVDAS onset. We purified an ADNP-KDM1A-GTF2I (AKG) protein complex from hNSCs and show that it targets transposable elements (TEs) to repress nearby gene transcription. Upon ADNP KO, KDM1A binding is lost at promoters targeted by AKG, pointing to ADNP as the anchoring subunit of the AKG complex. HVDAS cortical organoids show impaired progenitor proliferation and accelerated neuronal differentiation, coupled with a sustained upregulation of neurogenesis transcriptional programs, including key transcription factors normally repressed by AKG. This work suggests that the AKG complex acts as the relevant ADNP unit in the molecular onset of HVDAS.

neuroscience↗

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

Nucleoporin Nsp1 surveils the phase state of FG-Nups

Transport through the NPC relies on intrinsically disordered FG-Nups forming a selective barrier. Away from the NPC, FG-Nups readily form condensates and aggregates, and we address how this behavior is surveilled in cells. FG-Nups, including Nsp1, together with nuclear transport receptor Kap95, form a native cytosolic condensate in yeast. In aged cells this condensate disappears as cytosolic Nsp1 levels decline. Biochemical assays and modeling show that Nsp1 is a modulator of FG-Nup liquid-liquid phase separation, promoting a liquid-like state. Nsp1s presence in the cytosol and condensates is critical, as a reduction of cytosolic levels in young cells induces NPC assembly and transport defects and a general decline in protein quality control, all quantitatively mimicking aging phenotypes. Excitingly, these phenotypes can be rescued by cytosolic Nsp1. We conclude that Nsp1 is a phase state regulator that surveils FG-Nups and impacts general protein homeostasis. HighlightsO_LINups form native cytosolic condensates C_LIO_LINsp1 reduction mimics NPC aging phenotypes C_LIO_LINsp1 acts as phase state modulator of FG-Nups C_LIO_LINsp1 shares surveillance function with classical chaperones C_LI

cell biology↗

bioRxiv2023

Diameter Dependence of Transport through Nuclear Pore Complex Mimics Studied Using Optical Nanopores

The nuclear pore complex (NPC) regulates the selective transport of large biomolecules through the nuclear envelope. As a model system for nuclear transport, we construct NPC mimics by functionalizing the pore walls of freestanding palladium zero-mode waveguides with the FG-nucleoporin Nsp1. This approach enables the measurement of single-molecule translocations through individual pores using optical detection. We probe the selectivity of Nsp1-coated pores by quantitatively comparing the translocation rates of the nuclear transport receptor Kap95 to the inert probe BSA over a wide range of pore sizes from 35 nm to 160 nm. Pores below 55 {+/-} 5 nm show significant selectivity that gradually decreases for larger pores. This finding is corroborated by coarse-grained molecular-dynamics simulations of the Nsp1 mesh within the pore, which suggest that leakage of BSA occurs by diffusion through transient openings within the dynamic mesh. Furthermore, we experimentally observe a modulation of the BSA permeation when varying the concentration of Kap95. The results demonstrate the potential of single-molecule fluorescence measurements on biomimetic NPCs to elucidate the principles of nuclear transport.

biophysics↗

bioRxiv2022

Liquid-liquid phase separation of intrinsically disordered FG-Nups is driven by highly-dynamic hydrophobic FG-motifs

The intrinsically disordered FG-Nups in the NPC central channel can undergo liquid-liquid phase sepration (LLPS) into liquid condensates that display NPC-like permeability barrier properties. Here we present LLPS characteristics of each of the disordered FG-Nups of the yeast NPC. Using molecular dynamics simulations at amino acid resolution, FG-Nup condensates are studied and the main physicochemical driving forces for FG-Nup LLPS are identified. We show that FG-motifs that are predominantly present in the disordered domain of FG-Nups act as highly-dynamic hydrophobic stickers that are essential for the formation of stable liquid-like condensates. Next to that, we study LLPS of an FG-Nup mixture that resembles the NPC stoichiometry and observe that an NPC condensate is formed containing multiple types of FG-Nups. We find that the LLPS of this NPC condensate is also driven by FG-FG interactions, similar to the homotypic FG-Nup condensates. Based on the observed LLPS behavior, we categorize the different FG-Nups of the yeast NPC into two classes: The GLFG-Nups located in the central channel of the NPC phase separate into liquid-like condensates, forming a high-density cohesive barrier that can exclude inert particles. The FG-Nups at the entry and exit of the NPC channel, containing no GLFG-motifs, do not phase separate and possibly form a repulsive barrier by entropically excluding inert particles.

biophysics↗