How the ribosome starts sliding instead of walking

Max Planck Researchers unravel how the ribosome slides along non-coding mRNA

June 06, 2019

When synthesizing proteins, ribosomes move in exact small steps over long distances along a messenger RNA (mRNA). At certain sites, ribosomes stumble and start sliding before they land at a defined site and resume their accurate work. Marina Rodnina and her team at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen have now solved the question what makes the ribosome slide.

Ribosomes are the macromolecular machines that synthesize proteins according to the genetic blueprint stored in the DNA. Copies of the DNA, the mRNAs, deliver the information blueprints to the ribosome. Three nucleotides of the mRNA, called a codon, encode one amino acid, which are the building blocks of proteins. Each codon is decoded with the help of a transfer RNA (tRNA), which delivers the respective amino acid to the ribosome. The region of an mRNA between a start codon and a stop codon encodes for a protein and is called open reading frame (ORF).

Steps of three bases at a time

The ribosome usually moves forward from the start to the stop codon on the mRNA in exact steps of one codon at a time. For each cycle of protein synthesis, a tRNA delivers an amino acid to the ribosome and the peptide grows by one amino acid. Then, the ribosome moves one codon further on the mRNA with the help of a protein called elongation factor G (EF-G) in order to read the next codon. For each step, EF-G has to hydrolyze an energy-rich molecule called GTP to promote fast forward movement. To ensure that the protein is correctly produced, it is crucial that the ribosome moves by exactly one codon at each step.

When the ribosome stumbles

Remarkably, during the translation of particular mRNAs ribosomes slide over a non-coding region within an ORF to synthesize a single protein in a process called translational bypassing. The best-characterized example of bypassing is the gene 60 mRNA of bacteriophage T4. The ribosome reads the first 46 mRNA codons of the ORF up to the triplet coding for the amino acid glycine. The subsequent codon is a stop codon, but instead of terminating protein synthesis, the ribosome takes off and slides over a 50 nucleotides-long non-coding gap. It lands again at a distal glycine codon, and resumes translation to the end of the ORF. 

Model of translational bypassing. The ribosome (grey and yellow) is forced into a hyper-rotated state by the growing protein (green) and stem-loop in the messenger RNA (red). Elongation factor G (cyan) promotes take off and sliding. At the landing site the ribosome resumes translation.

What trips and shoves the ribosome

Combining biochemical and single-molecule approaches, Max Planck Director Marina Rodnina and her team have now unraveled how bypassing is initiated and driven. Residues of the synthesized peptide together with an mRNA stem-loop at the take-off site induce an unusual, hyper-rotated state of the ribosome. In this situation EF-G triggers ribosome take-off by shoving the stem-loop, akin of a tRNA in regular translocation. During bypassing EF-G hydrolyzes close to two molecules of GTP per nucleotide of the non-coding gap. The hyper-rotated conformation of the ribosome is also observed with ribosomes stalled by other mRNA sequences, suggesting common ribosome dynamics during translation stalling. These results demonstrate a new function of EF-G in promoting ribosome sliding along the mRNA, in contrast to a codon-wise ribosome movement during normal translation, and suggest a mechanism by which ribosomes could traverse untranslated parts of mRNAs. (Frank Peske)

Model of how the ribosome takes off for bypassing


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