Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.

ABSTRACT: G4C2 and G2C4 repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are the most common cause of genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), or c9ALS/FTD. The gene is bidirectionally transcribed, producing G4C2 repeats [r(G4C2)exp] and G2C4 repeats [r(G2C4)exp]. The c9ALS/FTD repeat expansions are highly structured, and structural studies showed that r(G4C2)exp predominantly folds into a hairpin with a periodic array of 1 × 1 G/G internal loops and a G-quadruplex. A small molecule probe revealed that r(G4C2)exp also adopts a hairpin structure with 2 × 2 GG/GG internal loops. We studied the conformational dynamics adopted by 2 × 2 GG/GG loops using temperature replica exchange molecular dynamics (T-REMD) and further characterized th

SUBMITTER: Taghavi A 

PROVIDER: S-EPMC10287959 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature