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Nat Struct Mol Biol. 2019 Nov 25. doi: 10.1038/s41594-019-0331-x. [Epub ahead of print]

Mechanism of ribosome stalling during translation of a poly(A) tail.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge, UK.
2
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Applied Physics, Stanford University, Stanford, CA, USA.
4
Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
5
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
6
MRC Laboratory of Molecular Biology, Cambridge, UK. rhegde@mrc-lmb.cam.ac.uk.

Abstract

Faulty or damaged messenger RNAs are detected by the cell when translating ribosomes stall during elongation and trigger pathways of mRNA decay, nascent protein degradation and ribosome recycling. The most common mRNA defect in eukaryotes is probably inappropriate polyadenylation at near-cognate sites within the coding region. How ribosomes stall selectively when they encounter poly(A) is unclear. Here, we use biochemical and structural approaches in mammalian systems to show that poly-lysine, encoded by poly(A), favors a peptidyl-transfer RNA conformation suboptimal for peptide bond formation. This conformation partially slows elongation, permitting poly(A) mRNA in the ribosome's decoding center to adopt a ribosomal RNA-stabilized single-stranded helix. The reconfigured decoding center clashes with incoming aminoacyl-tRNA, thereby precluding elongation. Thus, coincidence detection of poly-lysine in the exit tunnel and poly(A) in the decoding center allows ribosomes to detect aberrant mRNAs selectively, stall elongation and trigger downstream quality control pathways essential for cellular homeostasis.

PMID:
31768042
DOI:
10.1038/s41594-019-0331-x

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