Repeat-expanded C9orf72 mRNA engages the human ribosome to initiate non-AUG translation
摘要
Expanded hexanucleotide repeats in C9orf72 produce toxic proteins through repeat-associated non-AUG (RAN) translation, yet how repeat RNAs engage the eukaryotic initiation machinery has remained unresolved. Here we determine cryo-electron microscopy structures of human translation initiation complexes assembled on a (G4C2)₉₆ repeat mRNA. The transcript enters the canonical initiation pathway but accumulates in a normally transient 48S intermediate. A near-cognate CUG codon is decoded within a Kozak-like context in the standard decoding centre, while the repeat RNA simultaneously forms an anchoring contact with the 40S ribosomal head outside the mRNA channel. Together these features prolong the lifetime of a scanning-to-recognition transition intermediate and convert it into a productive start state without bypassing canonical initiation. RAN translation therefore arises not from an alternative initiation mechanism but from stabilisation of a latent non-AUG-competent state intrinsic to the ribosome. This framework links repeats expansion pathology to modulation of initiation dynamics and provides a structural basis for selectively suppressing pathogenic protein synthesis.
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