Biology subjects

Siahaan, V.

Publications and source records attributed to Siahaan, V..

7 recordsLinked to original sources

bioRxiv2026

Surface-induced tau condensation generates a selective microenvironment around microtubules

Tau is a neuron-specific microtubule-associated protein that can self-associate into pathological insoluble aggregates or phase separate into condensates whose (patho)physiological role is debated. Recent studies suggest that intracellular surfaces can locally promote biomolecular condensation, even at low molecular concentrations. While microtubules in neurons provide an abundant tau-interaction surface, their role in tau phase separation remains unclear. Through a dialogue between experiments and theory, we demonstrate that tau forms multilayered condensates on microtubules at physiological concentrations via a prewetting-like transition. Concomitant tau-microtubule and tau-tau interactions explain the experimentally observed cooperative binding of the innermost tau layer directly adsorbed to the microtubule. The formation of this layer is dictated by the spacing of tubulin dimers within the microtubule lattice. Additional tau layers, driven by tau-tau interactions and independent of lattice spacing, are finite in thickness and unstable away from the microtubule surface. While the microtubule-adsorbed tau can selectively restrict proteins from the microtubule surface, the multilayered tau condensates can recruit tau interactors, such as RNA or soluble tubulin, highlighting the distinct roles of the condensate layers. Our results suggest that a prewetting-like transition constitutes a general physical mechanism for organizing liquid-like biomolecular layers of defined composition on charged intracellular surfaces.

biophysics↗

bioRxiv2025

Microtubule remodeling by the innate immune factor Trim69 compromises dynein-dependent migration of HIV virion cores towards the nucleus

Like many viruses, HIV relies on the microtubule (MT) cytoskeleton for successful infection. MT-associated proteins (MAPs) regulate MT functions and thus bear the potential to modulate viral infection. However, while several MAPs are known to exert pro-viral effects on HIV, little is known about antiviral ones. We previously described the Tripartite motif protein 69 (Trim69) as an innate immune factor that remodels MTs, leading to inhibition of a broad spectrum of viruses, including HIV. Through in silico modeling, TIRF microscopy and cell-based assays, we determine that Trim69 binding to MTs is determined by a basic surface in its SPRY domain that interacts with the C-terminal tails of tubulins. This surface is conserved among mammalian Trim69s and is critical for its functions. We demonstrate that by binding and remodeling MTs, Trim69 inhibits the docking and the migration of virion cores on MTs by promoting the stalling of the dynein/dynactin motor complexes. Altogether, these findings shed light on a novel mechanism of viral defense that involves an innate immune regulation of the MT cytoskeleton.

cell biology↗

bioRxiv2024

A floor-field model of tau-taxol competition explains tau envelope dynamics on taxol-stabilized microtubules

Tau is a microtubule-associated protein (MAP) that is highly expressed in neurons. Recent in-vitro studies have shown that tau molecules can segregate into cohesive envelopes on paclitaxel (taxol) stabilized microtubules. These envelopes act as selective barriers gating the motor transport and protecting microtubules against the action of severing enzymes. However, the mechanisms underlying the formation of these envelopes remain unclear. Recent in vitro reconstitution assays revealed that the formation of tau envelopes induces a compaction of the underlying microtubule lattice, whereas taxol binding induces lattice expansion, indicating competitive binding between tau and taxol on microtubules. In this study, we use physical modeling to investigate how this competition between tau and taxol regulates the formation of tau envelopes. Our model includes static and dynamic floor-fields, concepts adapted from pedestrian dynamics. By comparing our simulation results with experimental data, we demonstrate that tau-taxol competition on the microtubule lattice is sufficient to explain the features of the formation and disassembly of tau envelopes. Notably, tau-tau interactions are not necessary to account for the steadiness of these envelopes.

biophysics↗

bioRxiv2024

Tau phosphorylation impedes functionality of protective tau envelopes

Tau, an axonal microtubule-associated protein, is a critical regulator of microtubule function and stability. Tau interaction with microtubules is regulated by tau phosphorylation. Tau hyperphosphorylation is implicated in microtubule destabilization related to neurodegenerative disorders. How tau phosphorylation leads to microtubule destabilization is however unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration, could be explained by the disassembly and impaired functionality of the tau envelopes.

cell biology↗

bioRxiv2021

Microtubule Lattice Spacing Governs Cohesive Envelope Formation of Tau Family Proteins

Tau is an intrinsically-disordered microtubule-associated protein (MAP) implicated in neurodegenerative disease. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive "envelopes" around microtubules. Envelopes differentially regulate lattice accessibility for other MAPs, but the mechanism of envelope formation remains unclear. Here, we find that tau envelopes form cooperatively, locally altering the spacing of tubulin dimers within the microtubule lattice. Envelope formation compacted the underlying lattice, whereas lattice extension induced tau-envelope disassembly. Investigating other members of the tau-MAP family, we find MAP2 similarly forms envelopes governed by lattice-spacing, whereas MAP4 cannot. Envelopes differentially biased motor protein movement, suggesting that tau family members could spatially divide the microtubule surface into functionally distinct segments. We conclude that the interdependent allostery between lattice-spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.

biophysics↗

bioRxiv2020

Anillin propels myosin-independent constriction of actin rings

Constriction of the actin cytokinetic ring is an essential step of cell division. In a generally accepted view, the constriction is driven by relative sliding of actin filaments propelled by myosin motors. However, in multiple organisms, the ring constriction is myosin independent. How actin rings constrict in the absence of motor activity remains unclear. Here, we demonstrate that actin contractility can be propelled by anillin, a diffusible non-motor actin crosslinker, localising to the cytokinetic ring. We in vitro observed the formation and constriction of rings comprising multiple actin filaments bundled by anillin. Rings constricted due to anillin-generated forces maximising the overlap lengths between the filaments. Actin disassembly promoted constriction. We propose that actin crosslinkers, generating forces complementary to molecular motors, contribute to the contractility of diverse actin structures, including the cytokinetic ring.

cell biology↗

bioRxiv2018

Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

Tau is an intrinsically disordered protein, which diffuses on microtubules. In neurodegenerative diseases collectively termed tauopathies, tau malfunction and its detachment from axonal microtubules is correlated with microtubule degradation. It is known that tau can protect microtubules from microtubule-degrading enzymes, such as katanin. However, how tau can fulfill such regulative function is still unclear. Using in vitro reconstitution, we here show that tau molecules on microtubules cooperatively form islands of an ordered layer with regulatory qualities distinct from a comparably dense layer of diffusible tau. These islands shield the microtubules from katanin and kinesin-1 but are penetrable by kinesin-8 which causes the islands to disassemble. Our results indicate a new phase of tau, constituting an adjustable protective sheath around microtubules.

biophysics↗