Cells are covered by a lipid membrane that gives them structure and provides a barrier between the cell and its environment. However, evidence has recently emerged to suggest that these membranes do more than just provide protection—they also influence the behavior of the protein receptors embedded within them.
A new study by MIT chemists adds further support to this idea. The researchers found that changing the composition of the cell membrane can alter the function of a membrane receptor that promotes proliferation.
The epidermal growth factor receptor (EGFR) can be locked into an overactive state when the cell membrane has a higher than normal concentration of negatively charged lipids, the researchers found. This may help explain why cancer cells with high levels of these lipids enter a highly proliferative state that allows them to divide uncontrollably.
The longstanding dogma of what a membrane does is that it is simply a scaffold, an organizational structure. However, there have been increasing observations suggesting that perhaps these membrane lipids actually play a role in receptor function.”
Gabriela Schlau-Cohen, the Robert T. Haslam and Bradley Dewey Professor of Chemistry at MIT and the study’s senior author
The findings open up the possibility of discovering new ways to treat tumors by neutralizing the negative charge, which can reduce EGFR signaling, he adds.
Shwetha Srinivasan PhD ’22 is the lead author of the paper, which appears in the journal eLife. Other authors include former MIT postdocs Xingcheng Lin and Raju Regmi, Xuyan Chen PhD ’25, and Bin Zhang, associate professor of chemistry at MIT.
Receptor dynamics
The EGF receptor, found on cells that line the body’s surfaces and organs, is one of several receptors that help control cell growth. Some types of cancer, especially lung cancer and glioblastoma, overexpress the EGF receptor, which can lead to uncontrolled growth.
Like most receptor proteins, EGFR spans the entire cell membrane. Until recently, it has been difficult to study how signals are transmitted throughout the receptor because of the difficulty of making membranes that have proteins that run all the way through and then studying both ends of those proteins.
To facilitate the study of these signaling processes, Schlau-Cohen’s lab uses nanodiscs, a special type of self-assembling membrane that mimics the cell membrane. In making these discs, the researchers can embed receptors in 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 the receptor changes under different conditions. Single molecule FRET allows them to measure the distance between different parts of the protein by labeling them with fluorescent labels and then measuring how fast energy travels between the labels.
In previous work, Schlau-Cohen and Zhang used single-molecule FRET and molecular dynamics simulations to reveal what happens when EGFR binds to EGF. They found that this binding causes the transmembrane part of the receptor to change shape, and that the shape change activates the part of the receptor that extends inside the cell to activate cellular machinery that stimulates growth.
Stuck in hyperactive mode
In the new study, the researchers used a similar approach to investigate how changing membrane composition affects receptor function. First, they investigated how increased levels of negatively charged lipids would affect the cell membrane and EGFR function.
Normally, about 15 percent of the cell membrane is made up of negatively charged lipids. The researchers found that membranes with negatively charged lipids in the range of 15 to 30 percent behaved normally, but if that level reached 60 percent, then the EGFR receptor would lock into an active state.
In this state, the pro-growth signaling pathway is continuously activated, even when no EGF is bound to the receptor. Many cancer cells show elevated levels of these lipids, and this mechanism could help explain why these cells can grow uncontrollably, says Schlau-Cohen.
“If the membrane has high levels of negatively charged lipids, then it’s always in this open conformation. It doesn’t matter if the ligand is bound or not,” he says. “It’s always in the conformation 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 increased cholesterol levels, they found that the membranes became more rigid, and this rigidity suppressed EGFR signaling.
The research was funded by the National Institutes of Health and the MIT Department of Chemistry.
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