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NIH Research Matters

December 14, 2009

Protein-Making Errors May Help Defend Cells

Anyone who's taken a biology class knows that a gene's sequence precisely dictates the order of amino acids that must be linked together to make a protein. A new study reveals that, in the face of an invading virus or bacteria—or an irritating chemical—the cell's protein-making machinery goes off-script, inserting more of an amino acid known to help defend proteins against damage.

Illustration of a ribosome translating mRNA code into protein.

Translation. The ribosome matches tRNAs (red, blue and bright green) to their complementary sequences in mRNA (multicolored strand below). Amino acids are transferred onto the emerging protein chain (yellow). Image courtesy of the Medical Research Council Lab of Molecular Biology, all rights reserved by Wellcome Images.

Proteins are made through a process called translation. First, the gene's DNA sequence is copied into RNA, a similar but less stable molecule. This "messenger RNA" (mRNA) travels to the ribosome, the molecular machine that synthesizes proteins. Another type of RNA, called transfer RNA (tRNA), binds to amino acids. There are 20 families of tRNA, one for each of the amino acids. The ribosomes match the tRNAs to their complementary mRNA sequences, thus "reading" the mRNA sequence, and stitch the amino acids together to make proteins.

Accuracy in this process is essential, since mistakes can result in proteins that don't work or, worse, interfere with cell function. One step that's crucial is aminoacylation, the attachment of amino acids to their proper tRNAs. In controlled laboratory experiments, the enzymes that perform this task make only one mistake in every 50,000 couplings. The accuracy of aminoacylation inside living cells, however, was unknown. A team led by Dr. Tao Pan at the University of Chicago and Dr. Jonathan Yewdell at NIH's National Institute of Allergy and Infectious Diseases (NIAID) set out to measure the accuracy of aminoacylation in living cells and animals.

In the November 26, 2009, issue of Nature, the team described a new method that can measure the accuracy of aminoacylation for 6 of the 20 amino acids. Results for 5 of the amino acids were as expected. Surprisingly, about 1% of the amino acid methionine was attached to the "wrong" tRNAs, or misacylated, in both cells in tissue culture and liver cells in a living mouse.

Remarkably, when the cells were stressed—by exposure to viral or bacterial components, or a toxic chemical such as hydrogen peroxide—up to 14% of the methionine was misplaced onto other tRNAs. These methionine-misacylated tRNAs, the researchers showed, were used in translation so that higher levels of methionine were incorporated into new proteins than the genetic code specified.

"The meaning of what we've discovered is uncertain at this point," Yewdell says, "but we have an intriguing hypothesis. Stressors trigger the cell to make what are known as reactive oxygen species. These small molecules are important messengers, but they can also damage proteins." Methionine, he explains, is known to play a "bodyguard" role in proteins, serving as a sort of target for reactive oxygen species that cells can easily repair.

Methionine-misacylation, then, may benefit the cell by protecting proteins from reactive oxygen species. Indeed, in follow-up experiments, the misacylation was blocked by a compound that inhibits cells from generating reactive oxygen species, implicating the molecules as the trigger for misacylation.

These results highlight the idea that genes can be read in different ways, Yewdell points out. "We found if you stress the cells in a certain way, the code for methionine changes," he says. He adds that other examples of cells going "off-code" are likely to be found in the future.

—by Harrison Wein, Ph.D.

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

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This page last reviewed on December 3, 2012

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