Multi-Domain Interplay Controls Full-Length TDP-43 Phase Separation and Condensate Dynamics
- 1Faculty of Biology, Institute of Molecular Physiology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Institute of Molecular Biology (IMB), 55128 Ma
Abstract
TDP-43 (TAR DNA-binding protein 43) is a 414-amino acid protein with a structured N-terminal domain (NTD), two RNA recognition motifs (RRM1 and RRM2), and a long disordered C-terminal low complexity domain (LCD). TDP-43 forms phase-separated condensates as part of its physiological function in RNA processing. However, aberrant TDP-43 condensation, changes in condensate material properties, and subsequent aggregation are linked to the development of neurodegenerative diseases. Using explicit-solvent, near-atomic resolution coarse-grained simulations we demonstrate how the interplay among different domains drives phase separation of the full-length protein.We directly capture how the secondary structure of a conserved helix in the LCD modulates phase separation, and follow the effect of phosphomimicking mutations on the condensation of full-length TDP-43. C-terminal phosphomimicking mutations rewire the interactions of the LCD by increasing solvation locally and enhancing Na+ binding to the LCD. Our simulations and in vitro experiments emphasize the importance of the aromatic residues in the LCD but also of N-terminal residues 1-101 including the NTD for full-length TDP-43 condensation. With a Go-type approach we capture not just conformational flexibility but also specific dimer formation through NTD-NTD interactions and how they modulate the phase behavior as well as the dynamic and interfacial properties of full-length TDP-43 condensates.
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BibTeX
@misc{ping2026multidomain,
title = {{Multi-Domain Interplay Controls Full-Length TDP-43 Phase Separation and Condensate Dynamics}},
author = {X. Ping and R. G. M. Badr and S. Hutten and X. Chen and L. Baltz and M. Yadav and J. S. Hoeppner and F. Schmid and D. Dormann and L. S. Stelzl},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.03.729912},
url = {https://www.biorxiv.org/content/10.64898/2026.06.03.729912v4},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Multi-Domain Interplay Controls Full-Length TDP-43 Phase Separation and Condensate Dynamics
AU - X. Ping
AU - R. G. M. Badr
AU - S. Hutten
AU - X. Chen
AU - L. Baltz
AU - M. Yadav
AU - J. S. Hoeppner
AU - F. Schmid
AU - D. Dormann
AU - L. S. Stelzl
PY - 2026
DA - 2026/06/03
PB - bioRxiv
DO - 10.64898/2026.06.03.729912
UR - https://www.biorxiv.org/content/10.64898/2026.06.03.729912v4
AB - TDP-43 (TAR DNA-binding protein 43) is a 414-amino acid protein with a structured N-terminal domain (NTD), two RNA recognition motifs (RRM1 and RRM2), and a long disordered C-terminal low complexity domain (LCD). TDP-43 forms phase-separated condensates as part of its physiological function in RNA processing. However, aberrant TDP-43 condensation, changes in condensate material properties, and subsequent aggregation are linked to the development of neurodegenerative diseases. Using explicit-solvent, near-atomic resolution coarse-grained simulations we demonstrate how the interplay among different domains drives phase separation of the full-length protein.We directly capture how the secondary structure of a conserved helix in the LCD modulates phase separation, and follow the effect of phosphomimicking mutations on the condensation of full-length TDP-43. C-terminal phosphomimicking mutations rewire the interactions of the LCD by increasing solvation locally and enhancing Na+ binding to the LCD. Our simulations and in vitro experiments emphasize the importance of the aromatic residues in the LCD but also of N-terminal residues 1-101 including the NTD for full-length TDP-43 condensation. With a Go-type approach we capture not just conformational flexibility but also specific dimer formation through NTD-NTD interactions and how they modulate the phase behavior as well as the dynamic and interfacial properties of full-length TDP-43 condensates.
ER -