Error correction in nature's nanotechnology

The ribosome has been an inspiration to many in nanotech as one example of a molecular machine system that executes a function—adding amino acids one at a time to a growing polypeptide —as programmed by a molecular instruction tape—a messenger RNA molecule. So it interesting is to discover that the ribosome has a previously unsuspected method of error correction—in this case monitoring the fidelity of protein synthesis after the peptide bond is formed. From Johns Hopkins Medical Institutions “Lost in Translation: Perfectionist protein-maker trashes errors

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 this week in Nature [abstract], 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 which, 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,” says Rachel Green, a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the Johns Hopkins University School of Medicine. “There’s no second chance.”

Previously, Green says, 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 says. “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 adds.

To their 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 says is “shocking” and reveals just how much of a stickler the ribosome is about high-fidelity protein synthesis.

The surprising observation is that a single misincorporation changes the activity of the ribosome, leading to a huge increase in the termination of proteins that contain errors. Perhaps the next question is what change in structure is caused by misincorporation and how does this change the ribosome activity? (Credit: Science Daily)

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