Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation.

ABSTRACT: Deposits of aggregated TAR DNA-binding protein 43 (TDP-43) in the brain are associated with several neurodegenerative diseases. It is well established that binding of RNA/DNA to TDP-43 can prevent TDP-43 aggregation, but an understanding of the structure(s) and conformational dynamics of TDP-43, and TDP-43-RNA complexes, is lacking, including knowledge of how the solution environment modulates these properties. Here, we address this challenge using hydrogen-deuterium exchange-mass spectrometry. In the presence of RNA olignoucleotides, we observe protection from exchange in the RNA recognition motif (RRM) domains of TDP-43 and the linker region between the RRM domains, consistent with nucleic acid binding modulating interdomain interactions. Intriguingly, at elevated salt concentrations, th

SUBMITTER: Minshull TC 

PROVIDER: S-EPMC11638948 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature