Researchers develop new technology to identify lipids that interact with membrane proteins

In a recent study published in the Journal of the American Chemical Society, researchers from the University of Arizona developed a new measurement tool called a lipidomic lipid exchange-mass spectrometry (LX-MS) that studies the interaction between lipids and membrane proteins. 

LX-MS provides researchers with detailed quantitative information analysis of hundreds of kinds of lipids and their roles in biological processes.

“Our initial goal is understanding the molecular mechanism of how membrane proteins select specific lipids from their complex local environment,” said the publication’s lead author, Michael T. Marty, PhD, associate professor in the University of Arizona Department of Chemistry and Biochemistry and a member of the UArizona Cancer Center. “Our larger goal is to understand how global changes in lipid metabolism, driven by diet, disease or aging, cause local changes in specific membrane protein physiology.”

Lipids are basic building blocks of all cells and include fats, oils, waxes, cholesterols, and fat-soluble vitamins among other compounds. They perform many key functions in the human body. Lipids cannot be dissolved in water and store energy, act as vital hormones, and form membranes that surround and protect cells. Proteins that reside within the membrane control the flow of chemicals and information into and out of the cell. Importantly, scientists do not fully understand which of the thousands of lipids in the membrane bind to a particular membrane protein and how strong these interactions are. 

To study the lipid-protein communication, the researchers created two types of lipid nanoparticles. In one type, they insert their membrane protein target and a mixture of natural lipids. In the other type, they include lipids only. Over time, the lipids exchange between the two groups of nanoparticles.

“Any lipids that bind the protein are enriched in that population of nanoparticles, and we can detect that enrichment with lipidomic mass spectrometry,” Marty said. 

Marty said that this discovery could have a cancer connection. When a person has cancer, their lipid metabolism can be altered leading to significant changes in membrane lipids that can influence the actions of some membrane proteins.

“We are trying to connect the dots between these two points,” Marty said. “Our hypothesis is that global lipid changes can affect local membrane protein activity, which could cause meaningful physiological effects.”

He said that as an example, global changes in cholesterol levels have been shown to affect growth factor receptors in cells creating mutations that cause rapid division. Understanding which lipids interact with specific membrane protein targets is the first step to understanding these regulatory mechanisms. 

“It may be that understanding how this works could lead to new treatment strategies using diet or drugs to modulate lipids,” he said.

From their research, the investigators hope to classify more lipids by developing new mass spectrometry methods to help increase their ability to see and identify a broader range of lipids. 

“Our initial methods could identify hundreds of lipids, but we know we are missing some key classes,” Marty said. “We are also always pushing to study new membrane protein targets relevant to human disease.”