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

DOI: 10.1038/s41594-019-0331-x DOI Help

Authors: Viswanathan Chandrasekaran (MRC Laboratory of Molecular Biology) , Szymon Juszkiewicz (MRC Laboratory of Molecular Biology) , Junhong Choi (Stanford University School of Medicine) , Joseph D. Puglisi (Stanford University School of Medicine) , Alan Brown (Harvard Medical School) , Sichen Shao (Harvard Medical School) , V. Ramakrishnan (MRC Laboratory of Molecular Biology) , Ramanujan S. Hegde (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 26 , PAGES 1132 - 1140

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 17434

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.

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios III-Titan Krios III at Diamond

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