Cells are covered by lipid membranes, which give them structure and provide a barrier between the cell and its environment. However, evidence has recently emerged suggesting that these membranes do more than just provide protection; they also influence the behavior of protein receptors embedded in the membranes.
A new study by MIT chemists further supports that idea. Researchers have found that changing the composition of cell membranes can alter the function of membrane receptors that promote proliferation.
Researchers have found that when the concentration of negatively charged lipids in cell membranes is higher than normal, the epidermal growth factor receptor (EGFR) can become locked into a hyperactive state. This may help explain why cancer cells containing high levels of these lipids enter a highly proliferative state where they divide uncontrollably.
A long-held theory about the role of membranes is that they are simply scaffolds, tissue structures. However, a growing number of observations suggest that perhaps these membrane lipids actually play a role in receptor function. ”
Gabriella Schlau-Cohen, Robert T. Haslam and Bradley Dewey Professor of Chemistry at MIT and senior author of the study
This discovery opens the possibility of discovering new ways to treat tumors by neutralizing the negative charges that can inhibit EGFR signaling, she added.
Shwetha Srinivasan PhD ’22 is the lead author of the paper published in the journal. e-life. Other authors include former MIT postdocs Xingcheng Lin and Raju Regmi, Xuyan Chen PhD ’25, and MIT associate professor of chemistry Bin Zhang.
Receptor dynamics
The EGF receptor is one of many receptors found on cells lining the body’s surfaces and organs that help control cell growth. Some types of cancer, particularly lung cancer and glioblastoma, overexpress EGF receptors and can cause uncontrolled growth.
Like most receptor proteins, EGFR is spread throughout the cell membrane. Until recently, it has been difficult to study how signals are transmitted across receptors. The reason is that it has been difficult to create membranes through which proteins can penetrate and then study both ends of those proteins.
To facilitate the study of these signaling processes, Schlau-Cohen’s lab uses nanodiscs, a special type of self-assembled membrane that mimics cell membranes. When creating these discs, researchers can embed receptors into them, allowing the team to study the function of the full-length receptor.
Using a technique called single-molecule FRET (fluorescence resonance energy transfer), researchers can study how the shape of receptors changes under different conditions. Single-molecule FRET can be used to measure the distance between different parts of a protein by labeling them with fluorescent tags and measuring the rate at which energy transfers between the tags.
In previous work, Schlau-Cohen and Zhang used single-molecule FRET and molecular dynamics simulations to uncover what happens when EGFR binds to EGF. They found that this binding changes the shape of the transmembrane portion of the receptor, and that shape change causes the portion of the receptor to spread inside the cell, activating cellular machinery that stimulates proliferation.
become hyperactive
In the new study, the researchers used a similar approach to investigate how changes in membrane composition affect receptor function. First, we studied how elevated levels of negatively charged lipids affect cell membranes and EGFR function.
Normally, about 15 percent of cell membranes are composed of negatively charged lipids. The researchers found that membranes containing negatively charged lipids in the range of 15 to 30 percent worked normally, but when the level reached 60 percent, the EGFR receptor became locked in an active state.
In this state, growth-promoting signaling pathways are constantly turned on, even when EGF is not bound to its receptor. Many cancer cells show increased levels of these lipids, and this mechanism may help explain why these cells are able to proliferate unchecked, Schlau-Cohen says.
“If a membrane contains a large amount of negatively charged lipids, it will always be in an open conformation, whether or not a ligand is bound,” she says. “It’s always within that structure that tells the cell to grow, not just when EGF binds.”
The researchers also used this system to investigate the role of cholesterol in EGFR function. When the researchers created nanodiscs with elevated cholesterol levels, they found that the membranes became stiffer, and that this stiffness inhibited EGFR signaling.
This research was funded by the National Institutes of Health and the Massachusetts Institute of Technology Department of Chemistry.
sauce:
Massachusetts Institute of Technology
Reference magazines:
Srinivasan, S. Others. (2026). Active regulation of epidermal growth factor receptors by membrane bilayers. e-life. DOI: 10.7554/eLife.108789.3. https://elifesciences.org/articles/108789
