Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.

ABSTRACT: C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404, and especially at S409/S410, is in fact accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation

SUBMITTER: Haider R 

PROVIDER: S-EPMC10996529 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature