North Carolina State University scientists report the discovery of how a specific protein-protein interaction prevents the cell from turning one of its switches off, which leads to uncontrolled cell proliferation.
The researchers say that Raf secures one of the two so-called switch regions in mutated Ras, so that the second switch can act like a closed door that isolates the key area where the overall signal switch is located.
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. Mutation of this amino acid to 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,” says Carla Mattos, Ph.D, associate professor of structural and molecular biochemistry and the lead author of the paper. “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, mutation or not.”
The paper is published in the December 2007 edition of Structure.