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

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Abstract
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.
Funding Information
  • Japan Society for the Promotion of Science (17K07291)

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