Johns Hopkins Gazette | February 2, 2009
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The newspaper of The Johns Hopkins University February 2, 2009 | Vol. 38 No. 20
 
Lost in Translation — Perfectionist Protein Maker Trashes Errors

By Maryalice Yakutchik
Johns Hopkins Medicine

The enzyme machine that translates a cell's DNA code into the proteins of life is nothing if not an editorial perfectionist.

Johns Hopkins researchers, reporting Jan. 8 in Nature, have discovered a new "proofreading step" during which the suite of translational tools called the ribosome recognizes errors, just after making them, and definitively responds by hitting its version of a "delete" button.

It turns out, the Johns Hopkins researchers say, that the ribosome exerts far tighter quality control than anyone ever suspected over its precious protein products that, as workhorses of the cell, carry out the very business of life.

"What we now know is that in the event of miscoding, the ribosome cuts the bond and aborts the protein in progress, end of story," said Rachel Green, a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the School of Medicine. "There's no second chance."

Previously, Green said, molecular biologists thought the ribosome tightly managed its actions only prior to the actual incorporation of the next building block by being super selective about which chemical ingredients it allows to enter the process.

Because a protein's chemical "shape" dictates its function, mistakes in translating assembly codes can be toxic to cells, resulting in the misfolding of proteins often associated with neurodegenerative conditions. Working with bacterial ribosomes, Green and her team watched them react to lab-induced chemical errors and were surprised to see that the protein-manufacturing process didn't proceed as usual, getting past the error and continuing its "walk" along the DNA's protein-encoding genetic messages.

"We thought that once the mistake was made, it would have just gone on to make the next bond and the next," Green said. "But instead, we noticed that one mistake on the ribosomal assembly line begets another, and it's this compounding of errors that leads to the partially finished protein being tossed into the cellular trash," she said.

To the researchers' further surprise, the ribosome lets go of error-laden proteins 10,000 times faster than it would normally release error-free proteins, a rate of destruction that Green said is "shocking" and reveals just how much of a stickler the ribosome is about high-fidelity protein synthesis.

"These are not subtle numbers," she said, noting that there's a clear biological cost — but a necessary expense — for this ribosomal editing and jettisoning of errors.

"The cell is a wasteful system in that it makes something and then says, Forget it, throw it out," Green said. "But it's evidently worth the waste to increase fidelity. There are places in life where fidelity matters."

The research was funded by the National Institutes of Health with support from the Howard Hughes Medical Institute.

In addition to Green, Hani S. Zaher, also of Johns Hopkins, was author of the paper.

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