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Cellular processes, such as when to multiply, are often regulated by
switches that control the frequency and timing of interactions between
proteins. North Carolina State University scientists have discovered
the way in which a specific protein-protein interaction prevents the
cell from turning one of its switches off, leading to uncontrolled cell
proliferation – one of the hallmarks of cancer.
In a paper published in the December 2007 edition of the Cell Press
journal Structure, the NC State researchers show for the first time
that the interaction between a rogue version of a specific protein
called Ras and its binding partner protein Raf can block the switch
from being turned off.
The paper shows, says Dr. Carla Mattos, NC State associate professor
of structural and molecular biochemistry and the lead author of the
paper, that Raf secures one of the two so-called switch regions in Ras,
so that the second switch can act like a closed door that isolates the
key area where the overall signal switch is located. Mattos likens the
abnormal protein-protein interaction to having the light permanently
stuck on because the switch is inaccessible behind the closed door.
In the world of molecular biochemistry, Mattos explains,
instructions for the proliferation of cells are given by cascades of
protein-protein interactions controlled by on-off switches. The switch
is on when the proteins can interact – resulting in cell proliferation
– and off when they cannot. If access to the switch is blocked and the
switch is stuck on, cells begin to multiply incessantly.
There are 20 existing amino acids that can be joined into chains
that make up proteins. Each protein has a unique sequence of amino
acids. In the chain of 189 amino acids of which Ras is composed, the
position in question is at the 61st amino acid, which is normally a
glutamine known to help in turning the interaction switch off. Change,
or mutation, of this amino acid to an amino acid called leucine is a
commonly observed defect in cancer cells.
"The switch only gets stuck on when Raf is present and the defective
Ras has position 61 as a leucine or one of the few amino acids shown to
cause cell transformation, one of the properties observed in cancer,"
Mattos says. "For glutamine or the mutations that do not cause cell
transformation, the molecular door can fly open and allow access to the
switch – even when Raf is bound to Ras. The door can always open in the
absence of Raf."
The paper responds to a paradox that arose in the 1980s when
scientists compared the behavior of Ras mutants in cells versus in
solution, isolated from other cellular components including Raf. The
studies of Ras in solution suggested nothing special about the
mutations that cause cell transformation versus those that do not, as
any amino acid other than glutamine at position 61 made turning off the
Ras switch only 10 times slower, rather than blocking the switch.
Scientists did not understand why the isolated Ras mutants behaved
differently than the Ras mutants in their cellular environment.
Mattos, research associate Greg Buhrman and undergraduate student
Glenna Wink provide the answer to this paradox by showing that the
switch stays on when Raf binds Ras containing the leucine mutation and
that it can be turned off in the absence of Raf, although not at the
normal rate. In normal Ras the switch can be turned off either in the
presence or absence of Raf. The atomic resolution structures of the
rogue Ras proteins with strongly transforming mutations show that they
all keep the molecular door closed and the switch on in the same way.
The structures of the normal Ras and of a mutant known to have weak
transforming ability both have the molecular door open.
"We all knew that there had to be something in the cell not
accounted for by the studies in isolated Ras," Mattos says. "We now
know that at least part of that something is the Raf protein. When the
defective Ras encounters Raf, the switch becomes inaccessible and the
highly controlled cell proliferation system is broken, leading to
uncontrolled cell proliferation and cancer."
The study was funded by the National Institutes of Health.
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