Different recognition modes of G-quadruplex RNA between two ALS/FTLD-linked proteins TDP-43 and FUS

Amyotrophic lateral sclerosis/frontotemporal lobar degeneration-linked proteins, TDP-43 and fused in sarcoma (FUS), bind to G-quadruplex-containing mRNAs and transport them to distal neurites for local translation. The specificity and mechanism of G4-RNA binding, however, remain largely unsolved. Using purified full-length TDP-43 and FUS and a set of seven G4-DNA/RNA, we compared their recognition properties of G4-RNAs. Both TDP-43 and FUS recognized and bound to G4-DNA/RNAs, but the target selectivity differed between two proteins. TDP-43 recognized only parallel-stranded G4-DNA/RNAs, leading to stabilize the G4 conformation. In contrast, FUS bound to all three types, parallel, hybrid, and antiparallel, of G4-DNA/RNAs, resulting in deformation of the G4 structure. We then concluded that the target selectivity and the influence on G4 RNA structure differed between TDP-43 and FUS.