The research, published in the journal Nature Communications, focuses specifically on a scramblase protein named TMEM16F.
"Understanding how scramblases work is of great medical relevance," said Gustavo Vasquez, a postdoctoral researcher in the Department of Physics at Illinois and lead author of the study. "The abnormal activity or regulation of scramblases has been linked to several medical conditions, including neurological disorders, muscular dystrophies, and even certain types of cancer."
Scramblases reside in the cell membrane and function to maintain its equilibrium. They do so by flipping lipids (fatty acids) from one side of the membrane to the other. This action helps in the repair of damaged membranes.
"What we found is that scramblases generate membrane pores large enough to allow the entire lipid head group to go through," Vasquez said. "In fact, we were able to show that most of the lipids were flipped by this mechanism."
The researchers used a technique known as "Förster resonance energy transfer," or FRET, to measure the changes in the distance between two fluorescent dyes that were attached to the opposite sides of the membrane.
"By using this technique, we could see that the membrane was expanding and contracting," said Leonid Chernomordik, a professor of physics at Illinois and co-author of the study. "This change in membrane shape was not random, but rather followed a specific pattern."
The researchers believe that the scramblase works in a cooperative fashion, with multiple proteins working together to generate the membrane pores.
"It is likely that the scramblase proteins self-assemble into a larger complex that acts like a machine to flip the lipids," Vasquez said. "This finding has important implications for the design of drugs that target scramblases, as it suggests that drugs that target the assembly of the complex may be more effective than those that target the individual proteins."
The researchers are now working to understand the molecular structure of the scramblase complex and how it interacts with the cell membrane.
"This work is providing a solid foundation for understanding how these important proteins work and how their activity can be controlled," Chernomordik said.
