Study Finds Protein Chain Stabilizes Caveolae in the Cell Membrane

Cell membranes do more than form a barrier—they also control which molecules move in and out, and their structure reflects that complexity. One recurring feature is caveolae, small bottle-shaped indentations found in the outer membrane of nearly all cells in the body. Caveolae protect cells, particularly those lining blood vessels, from mechanical stress, function as signaling hubs that help regulate blood pressure, and allow cells to take in nutrients such as fatty acids. 

Researchers at the Max Delbrück Center have now worked out how these structures are held in place at the cell membrane. “A chain of protein molecules wraps around the neck of these bottle-shaped structures to support them,” explains Oliver Daumke, senior author of the study published in Nature Communications. The team determined the structure of this chain, which is built from a protein called EHD2. Daumke had previously shown that without EHD2, caveolae aren’t securely anchored to the membrane.

Using cryo-electron microscopy methods developed by co-author Mikhail Kudryashev's team, the researchers found that two EHD2 molecules combine into a dimer, forming individual links. “Certain parts of these EHD2 links then attach to one another, forming a chain,” explains first author Elene Vázquez-Sarandeses. “We were able to observe how this chain wrapped itself around the tubular membrane structures we used for our experiments.”

EHD2 consists of 540 amino acids, and the researchers found that the first 19 act as a spacer, ensuring only a single chain wraps around each caveola’s neck. “Without it, multiple chains align side by side, causing the caveolae to lose their typical shape and function,” Daumke says. Without a properly functioning EHD2 chain, the neck of the caveola grows progressively thinner and longer until the structure detaches from the membrane altogether.

The findings could eventually inform new approaches to treating lipid metabolism disorders by helping regulate how cells take up fat, the authors say. Faulty caveolae are also linked to diseases of the muscles, heart, blood vessels, lungs, and kidneys. “Without these invaginations, cells are less able to withstand mechanical stress. They’re also less able to regulate signaling processes,” Daumke explains. “That’s why tissues such as muscles, the heart, and blood vessels, which are constantly exposed to stress, are particularly vulnerable.” The team’s next step is to visualize EHD2 chains directly at the neck of a caveola in living cells, and then examine how the chains behave in cells with disrupted caveola function.