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.
Dr. Carla Mattos | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy