Picture a boxing match, Tao Pan said. A cell, facing viral or bacterial invasion, starts building new proteins, while the infection generates dangerous reactive oxygen species that rampage through the cell causing serious damage. When the new proteins meet the reactive oxygen species (ROS), they face off like welterweights circling each other in the ring – ROS dart in, trying to do damage to the protein’s most important sites, while the protein deflects attacks with an amino acid, called methionine, capable of absorbing those blows.
Cells can place protective methionines into proteins the old-fashioned way, by encoding for the amino acid in the DNA recipe. But in a paper published this week in the journal Nature, researchers from the University of Chicago and the National Institute of Allergy and Infectious Diseases describe a new, post-genetic way for cells to add methionine bodyguards to proteins when they are threatened: making purposeful mistakes.
To discover this useful fallibility, Pan – a professor of biochemistry and molecular biophysics at the University of Chicago – and graduate student Jeffrey Goodenbour developed a novel assay for measuring particular errors called misacylations. If you recall the central dogma of molecular biology, DNA is used to make protein via intermediaries called RNA. First, an RNA copy of the DNA gene for a particular protein is created, called messenger or mRNA. Then that mRNA moves to a cellular machine called a ribosome. Specific transfer RNAS – tRNAs – are then recruited to the ribosome, bringing along amino acids that are placed in order according to the mRNA recipe. After hundreds or downloadable software thousands of amino acids are arranged into a chain, you have a completed protein.
One would think it was a bad thing for mistakes to happen along this manufacturing process, and scientists have long believed that quality-control measures are in place to ensure that the proteins come out the way DNA says they should. One step that prevents mistakes is tRNA specificity – each of the 20 tRNA varieties can only bind to one type of amino acid. Occasionally, a tRNA grabs the wrong amino acid, an error called misacylation, but laboratory studies in artificial systems estimated that this mistake only happens about once every 10,000 times.
The keyword there is “artificial systems” – because when Goodenbour and Pan looked at the misacylation rate in live cells, it was much higher: 1 out of every 100 methionines was placed incorrectly, they found. And when the cell was stressed by a virus, bacteria, or a caustic chemical such as hydrogen peroxide, that methionine error rate went up even higher, with as many as 1 out of 10 off-recipe placements. That emergency measure would make new proteins more resistant to ROS damage when the cell needs them the most, Pan said.
“This mechanism allows every protein to get some protection,” Pan said. “The genetic code is considered untouchable, but this is a non-genetic strategy used in cells to create a bodyguard for proteins.”
The scientific question raised by this discovery is: why? Cells could more directly protect their proteins by loading them up with methionines through the DNA code, removing the need to rely on random “errors” imposed later in the translation process. But Pan proposes that very randomness as the secret weapon cells employ to make their proteins difficult targets for ROS attacks. By placing the protective methionines in different places in each protein, cells generate a diverse population of proteins each with their own unique set of armor – a strategy that would be impossible if translation of DNA into protein was perfect. Just like on the species level, diversity is one of the best defense against attack.
“This sounds chaotic and doesn’t make a lot of sense according to the textbook,” Pan said. “But this way the cells can always ensure that a subset of these proteins is somewhat less sensitive to the extra hits. I think that’s the most important part of this – to make every protein molecule different – and you cannot do this genetically.”