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Why the switch stays on
Date:12/12/2007

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 pr
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Contact: Dr. Carla Mattos
carla_mattos@ncsu.edu
919-513-2556
North Carolina State University
Source:Eurekalert

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