Mechanism of Ribosome Stalling by the AMD1 C-terminal Tail Arrest Peptide

Maldosevic, E.; Boiocchi, F. S.; Swirski, M. I.; Meiklejohn, K. A.; Yordanova, M. M.; Baranov, P.; Jomaa, A.

doi:10.1101/2025.11.16.688537

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bioRxiv · 10.1101/2025.11.16.688537

Mechanism of Ribosome Stalling by the AMD1 C-terminal Tail Arrest Peptide

Maldosevic, E.·Boiocchi, F. S.·Swirski, M. I.·Meiklejohn, K. A.·Yordanova, M. M.·Baranov, P.·Jomaa, A.

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Abstract

AMD1 encodes Adenosylmethionine decarboxylase 1 (AMD1), a key enzyme required for polyamine biosynthesis. A subset of ribosomes translating the AMD1 coding sequence (CDS) read through the stop codon and pause at the next in-frame stop codon 384 nucleotides downstream. The resulting C-terminal extension (C-tail) is universally conserved across all vertebrates, implying that its molecular function is critical to their fitness. Despite growing evidence that such cis-acting elements regulate translation of their genes, the molecular mechanism by which the C-tail mediates ribosome stalling remains unclear. Here, we determined the structure of the ribosome nascent chain complex paused by the AMD1 C-tail which traps eukaryotic release factor 1 (eRF1) with the ATP-binding cassette sub-family E member 1 (ABCE1). The nascent chain forms a molecular clamp that positions an arginine finger in the peptidyl-transferase center, occluding the accommodation of the eRF1 GGQ motif thereby hampering translation termination. Analysis of aggregated ribosome profiling data revealed several genes with a pattern of stop codon readthrough followed by ribosome stalling at a specific location, suggesting that regulatory readthrough-stall mechanisms may not be limited to AMD1.

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Maldosevic, E., Boiocchi, F. S., Swirski, M. I., Meiklejohn, K. A., Yordanova, M. M., Baranov, P., Jomaa, A.. 2025-11-16. Mechanism of Ribosome Stalling by the AMD1 C-terminal Tail Arrest Peptide. https://doi.org/10.1101/2025.11.16.688537

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