Detection of an Intermediate in the Unfolding Process of the N-Terminal Domain of TDP-43.

ABSTRACT: TAR DNA-binding protein 43 (TDP-43) is a nuclear protein accumulating in intraneuronal cytoplasmic inclusions associated with amyotrophic lateral sclerosis, frontotemporal lobar degeneration with tau-negative/ubiquitin-positive inclusions, and limbic-predominant age-related TDP-43 encephalopathy. Oligomerization of full-length TDP-43, driven by its N-terminal domain (NTD), is essential for its function, but aberrant self-assembly also promotes liquid-liquid phase separation and formation of solid inclusions. Building on recent all-atom molecular dynamics simulations and using various biophysical approaches, we identified a partially unfolded state accumulating during unfolding of TDP-43 NTD, before the major energy barrier of unfolding is crossed. Intrinsic fluorescence spectroscopy couple

SUBMITTER: Marzi I 

PROVIDER: S-EPMC11840787 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature