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Edited by Rachel Green, Johns Hopkins University, Baltimore, MD, and approved July 10, 2014 (received for review May 21, 2014)
Significance
Biological fitness is dependent on the accurate flow of genetic information from DNA to mRNA to protein. Breakdown in ribosome translational fidelity is detrimental because of its central role in the production of proteins. Altering the 3-base genetic code usually results in the expression of aberrant or nonsense proteins that are degraded. Here, we describe molecular snapshots of the ribosome in the process of decoding a 4-base codon by a frameshift suppressor tRNA that results in a +1-nt shift of the mRNA reading frame. Conformational dynamics of the anticodon stem loop seem to drive remodeling of the tRNA–mRNA interaction to promote the +1 movement, which we predict occurs after accommodation of the tRNA onto the ribosome.
Abstract
Maintenance of the correct reading frame on the ribosome is essential for accurate protein synthesis. Here, we report structures of the 70S ribosome bound to frameshift suppressor tRNASufA6 and N1-methylguanosine at position 37 (m1G37) modification-deficient anticodon stem loopPro, both of which cause the ribosome to decode 4 rather than 3 nucleotides, resulting in a +1 reading frame. Our results reveal that decoding at +1 suppressible codons causes suppressor tRNASufA6 to undergo a rearrangement of its 5′ stem that destabilizes U32, thereby disrupting the conserved U32–A38 base pair. Unexpectedly, the removal of the m1G37 modification of tRNAPro also disrupts U32–A38 pairing in a structurally analogous manner. The lack of U32–A38 pairing provides a structural correlation between the transition from canonical translation and a +1 reading of the mRNA. Our structures clarify the molecular mechanism behind suppressor tRNA-induced +1 frameshifting and advance our understanding of the role played by the ribosome in maintaining the correct translational reading frame.
Footnotes
↵1T.M. and J.A.D. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: christine.m.dunham{at}emory.edu.
Author contributions: T.M., J.A.D., and C.M.D. designed research; T.M., J.A.D., and S.J.M. performed research; T.M., J.A.D., and C.M.D. analyzed data; and T.M., J.A.D., and C.M.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The crystallography, atomic coordinates, and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4L47, 1VVJ, 4L71, 4LEL, 4LFZ, 4LNT, 4LSK, 4LT8, and 4P70).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1409436111/-/DCSupplemental.
Structures of 70S-+1 frameshift-prone tRNAs
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