How did the genetic code—DNA and RNA bases that assign a specific amino acid sequence to proteins—come into being? Numerous theories, all unproven, attempt to explain this mystery. Proposed in the mid-1960s by Carl Woese, the “stereochemical hypothesis” maintains that the code evolved as a result of RNA coming into direct contact with the amino acids it codes for. Another theory, proposed by Francis Crick, is that the code evolved from the last common universal ancestor and is an accident frozen in time.
A new bioinformatics study published in the October issue of Nucleic Acids Research suggests that messenger RNAs (mRNAs) and the proteins they code for bind to each other in a complementary fashion—a finding that furthers the stereochemical hypothesis, according to the study authors.
“What we hope our results will now do is reignite this discussion with a clear bias in the direction of the complementary stereochemical hypothesis by Woese,” noted senior author Bojan Zagrovic, a group leader at the Max F. Perutz Laboratories at the University of Vienna in Austria.
In recent years, researchers have found examples of mRNA-protein interactions involving metabolic enzymes and transcription factors, as well as other proteins that were not previously expected to bind mRNAs. A handful of proteins—such as thymidylate synthase, dihydrofolate reductase and p53—are known to bind to their cognate mRNAs, although the significance of these interactions is still unclear.
In the study, Zagrovic and postdoctoral researcher Anton Polyansky analyzed the interfaces between RNA and protein, for which 299 three-dimensional structures were available in the Protein Data Bank. They used a predetermined distance cutoff of 8 ångströms or less to identify RNA bases and amino acids that come into close contact and from this derived the preferences of the 20 natural amino acids for the 4 RNA bases.
At protein-RNA interfaces, amino acids tend to contact nucleotide bases that correspond with their own codons. The group also found a high level of matching between mRNA composition and corresponding amino acid stretches, especially those encoded by purines, when they analyzed the human proteome and the coding sequences of corresponding mRNAs from UniProtKB.
There are many scenarios where contact between mRNA and its protein could have functional significance, said Zagrovic. For some proteins, it could provide a means of translational control. “There’s a long list of proteins that do it,” he said. “It’s just that the physicochemical principles have not been elucidated.” In addition, the interactions could play a role in virus assembly, or in the making of P bodies, membrane-less compartments within cells that are rich with proteins and RNA.
The new study suggests that proteins bind their mRNAs, but the interactions might not be specific, the authors noted. “The biggest next frontier is trying to test some of these ideas experimentally,” said Zagrovic. “The question is, will a protein bind to its own mRNA?” The group plans to start with purified mRNA and protein before moving into cells. They also plan to examine whether unrelated mRNAs match up to a protein as well as cognate mRNAs do.
“Now with Bojan Zagrovic’s reopening of the debate, new ways of thinking are necessary and Carl Woese’s hypothesis is back on the agenda. The genetic code is for sure frozen but probably not accidentally,” said Renée Schroeder, a colleague at Max F. Perutz Laboratories in University of Vienna who was not involved with the study but is acknowledged in the paper. “Let’s see where Zagrovic’s research will take him.”
1. Polyansky AA, Zagrovic B. Evidence of direct complementary interactions between messenger RNAs and their cognate proteins. Nucleic Acids Res. 2013 Oct 1;41(18):8434-43. doi: 10.1093/nar/gkt618. Epub 2013 Jul 18.