When a ribosome cruises along messenger RNA (mRNA), it may stall at a particular codon, depending on which codons are nearby. In other words, codon context can influence the efficiency with which mRNA is translated and amino acids are attached to growing protein chains.
New details about codon-context effects have been uncovered by scientists based at the University of Utah. These scientists, Kelly T. Hughes, Ph.D., and Fabienne F.V. Chevance, Ph.D., report that mRNA translation at a given codon can be affected by the two previous codons. In addition, the scientists offer a model of protein elongation to explain how codon context can facilitate, or hinder, translation.
Biologists have long accepted that sets of three letters, called triplets or codons, are the fundamental unit of instruction telling the ribosome which particular amino acid to add to the growing protein chain. “We know it's a triplet code,” said Dr. Hughes. “That's been established since 1961. But there are certain things that happen in making protein from RNA that don't quite make sense.”
Drs. Hughes and Chevance worked with a gene in Salmonella that codes for the FlgM protein, which is a component of the bacteria's flagellum. A mutation that was defective in “reading” a specific codon in the flgM gene only affected FlgM protein production and not other genes that contained the same codon.
“That got us thinking,” noted Dr. Hughes. “Why is that particular codon in the flgM gene affected and not the same codon in the other genes? That's when we started thinking about context.”
The scientists summarized their work in a paper that appeared April 17 in the Proceedings of the National Academy of Sciences, in a paper entitled, “Case for the Genetic Code as a Triplet of Triplets.”
“The efficiency of translating a particular codon is influenced by the nature of the immediately adjacent flanking codons,” the article’s authors wrote. “A model explains these codon-context effects by suggesting that codon recognition by elongation factor-bound aminoacyl-tRNA is initiated by hydrogen bond interactions between the first two nucleotides of the codon and anticodon and then is stabilized by base-stacking energy over three successive codons.”
Changing the codon on one side of the defective codon resulted in a 10-fold increase in FlgM protein activity. Changing the codon on the other side resulted in a 20-fold decrease. And the two changes together produced a 35-fold increase. “We realized that these two codons, although separated by a codon, were talking to each other,” Dr. Hughes explained. “The effective code might be a triplet of triplets.”
Drs. Hughes and Chevance say that a triplet of triplets code might reframe how biologists study cancer genetics, for example, or other human genetic diseases for which triplet codon context may be more important than previously recognized.