This research project, led by Matthias Buck, professor of physiology and biophysics at the school of medicine, showed how cell membranes control the shape and function of an important cancer-causing protein. The findings were recently described in the journal Structure .
The protein, called K-Ras, attaches to cell membranes and causes healthy cell growth when it's activated by growth hormones secreted by the body. But mutated K-Ras proteins get further locked in the "on" position, causing rampant cell growth resulting in cancerous tumours. This is especially prevalent in pancreatic cancer, Matthias Buck said.
"The light switch is broken; it's on all the time", Matthias Buck explained.
For years, researchers have tried to find way to switch off mutated K-Ras proteins by interrupting growth signals reaching the proteins, Matthias Buck said. He and Zhen-Lu (Andrew) Li, a postdoctoral student in the physiology and biophysics department at the Case School of Medicine, tackled the problem by investigating how K-Ras attaches to cell membranes.
The researchers' year-long project found that the protein's function is heavily influenced by lipids, or fatty structures, on the cell membranes. This means that future cancer drugs may need to target both K-Ras and the cell membranes they are attached to, Matthias Buck said.
Matthias Buck and Zhen-Lu Li discovered that the composition of lipids in the cell membranes is what makes K-Ras proteins get stuck in the "on" position. If this type of membrane lipid could be kept away from cell membranes, that might prevent K-Ras proteins from flipping "on" and encouraging cancerous cell growth, Matthias Buck said.
Lipids are naturally occurring molecules that include fats and make up cell membranes.
K-Ras proteins is only 1/100,000th of an inch - or 30 atoms across - in size. To observe something that minuscule, researchers needed to use Case's nuclear magnetic resonance spectrometer, a device that can peer at molecules, Matthias Buck said.
Matthias Buck and Zhen-Lu Li spent months running real-time simulations on a specialized computer, dubbed Anton, at the Pittsburgh Supercomputer Center, which is a joint effort of Carnegie Mellon University and the University of Pittsburgh. They also used the High Performance Computing Cluster at Case and the Ohio Supercomputer Center in Columbus, Matthias Buck said.
Zhen-Lu Li's specialty was analyzing the supercomputers' results to reveal the larger picture, Matthias Buck said.
Through supercomputer simulations, Matthias Buck and Zhen-Lu Li saw that K-Ras isn't round, but pyramid-shaped with five surfaces that can interact with cell membranes. Supercomputer simulations allowed the researchers to predict, on the atomic level, how K-Ras oriented itself in relation to a cell membrane, as well as the membrane's behaviour.
Since lipids are related to fats, it's logical to ask if a patient's diet could affect the lipid-K-Ras interaction. "It doesn't work that way", Matthias Buck stated.
Instead, future research projects will search for tiny molecules that, when inserted, could turn K-Ras "off". These molecules could be the basis for a future medicine delivered directly to cancer cells, he said.