Desmin Mutations Disrupt Filament Elongation and Drive Polymorphic Aggregation
- 1Department of Physics, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany
Abstract
In muscle cells, desmin intermediate filaments form a cytoskeletal network that maintains the structural integrity and mechanical coupling of myofibrils. Dominant missense mutations in desmin cause myopathies characterized by intracellular protein aggregation. To explore the process of aggregate formation, we investigate the assembly kinetics of wild-type desmin and four disease-associated variants (N342D, L345P, R350P, and R406W) using dual-wavelength stopped-flow spectroscopy, complemented by atomic force microscopy and molecular dynamics simulations. At low ionic strength, all proteins form uniform tetramers. Increasing the ionic strength initiates assembly by rapid lateral association of tetramers into unit-length filaments (ULFs), followed by longitudinal elongation and radial filament compaction. R406W forms ULFs with wild-type-like kinetics, whereas N342D, L345P, and R350P exhibit delayed lateral assembly. After short filaments have formed, all four mutants diverge from productive filament maturation, but through distinct pathways. Quantitative analysis of atomic force microscopy images together with kinetic modelling of the spectroscopic data shows that wild-type filaments elongate continuously, whereas R406W filaments progressively associate into fibrillar clusters and cease elongating. By contrast, N342D, L345P, and R350P rapidly collapse into globular complexes that subsequently coalesce into larger aggregates. Molecular dynamics simulations indicate that the mutations differentially destabilize coil 2, which leads to local structural perturbations and mutation-specific assembly defects. Together, these findings identify early filament maturation - when elongating ULF-derived filaments would normally undergo radial compaction to form stable, mature filaments - as a critical time point in desmin assembly. At this stage, pathogenic mutations redirect the internal reorganization of the filament from productive stabilization toward mutation-specific structural collapse and aggregation.
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BibTeX
@misc{schween2026desmin,
title = {{Desmin Mutations Disrupt Filament Elongation and Drive Polymorphic Aggregation}},
author = {L. Schween and J.-P. Burchert and M. van der Heyden and D. Schultheis and N. Muecke and S. Koester and S. H. Strelkov and H. Herrmann and B. Fabry},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.22.740046},
url = {https://www.biorxiv.org/content/10.64898/2026.07.22.740046v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Desmin Mutations Disrupt Filament Elongation and Drive Polymorphic Aggregation
AU - L. Schween
AU - J.-P. Burchert
AU - M. van der Heyden
AU - D. Schultheis
AU - N. Muecke
AU - S. Koester
AU - S. H. Strelkov
AU - H. Herrmann
AU - B. Fabry
PY - 2026
DA - 2026/07/22
PB - bioRxiv
DO - 10.64898/2026.07.22.740046
UR - https://www.biorxiv.org/content/10.64898/2026.07.22.740046v2
AB - In muscle cells, desmin intermediate filaments form a cytoskeletal network that maintains the structural integrity and mechanical coupling of myofibrils. Dominant missense mutations in desmin cause myopathies characterized by intracellular protein aggregation. To explore the process of aggregate formation, we investigate the assembly kinetics of wild-type desmin and four disease-associated variants (N342D, L345P, R350P, and R406W) using dual-wavelength stopped-flow spectroscopy, complemented by atomic force microscopy and molecular dynamics simulations. At low ionic strength, all proteins form uniform tetramers. Increasing the ionic strength initiates assembly by rapid lateral association of tetramers into unit-length filaments (ULFs), followed by longitudinal elongation and radial filament compaction. R406W forms ULFs with wild-type-like kinetics, whereas N342D, L345P, and R350P exhibit delayed lateral assembly. After short filaments have formed, all four mutants diverge from productive filament maturation, but through distinct pathways. Quantitative analysis of atomic force microscopy images together with kinetic modelling of the spectroscopic data shows that wild-type filaments elongate continuously, whereas R406W filaments progressively associate into fibrillar clusters and cease elongating. By contrast, N342D, L345P, and R350P rapidly collapse into globular complexes that subsequently coalesce into larger aggregates. Molecular dynamics simulations indicate that the mutations differentially destabilize coil 2, which leads to local structural perturbations and mutation-specific assembly defects. Together, these findings identify early filament maturation - when elongating ULF-derived filaments would normally undergo radial compaction to form stable, mature filaments - as a critical time point in desmin assembly. At this stage, pathogenic mutations redirect the internal reorganization of the filament from productive stabilization toward mutation-specific structural collapse and aggregation.
ER -