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
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
"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
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.