How a protein shapes the cell membrane
Our cells’ membranes have many functions. They not only provide mechanical protection, but also precisely control which substances enter or leave the cells. If they fail to perform these tasks, disease can result. Their structure is correspondingly complex: The outer cell membrane, for example, often features bottle-shaped invaginations called caveolae. Among others, they protect the cells of blood vessels, which are frequently exposed to strong mechanical forces. In addition, caveolae serve as signaling centers that help regulate blood pressure. Cells also absorb nutrients — especially fatty acids — via caveolae.
Researchers have now discovered how caveolae — which are found in nearly all cells of our body — are stabilized to the outer cell membrane. “A chain of protein molecules wraps around the neck of these bottle-shaped structures to support them,” explains a Group Leader. They have now elucidated the structure of this protein chain. Previously they have shown that without the protein EHD2 — of which the chain is composed — caveolae are not securely anchored in the cell membrane.
The authors hope that the new study could help, for example, to regulate fat uptake by cells and thus lead to better treatment of lipid metabolism disorders. The work is published in “Nature Communications.”
The team developed new cryo-electron microscopy methods, which enabled them to resolve how two molecules of the EHD2 protein combine to form a dimer, thereby creating the individual chain links. “Certain parts of these EHD2 links then attach to one another, forming a chain,” explains another author. “We were able to observe how this chain wrapped itself around the tubular membrane structures we used for our experiments.”
EHD2 is a protein composed of 540 amino acids. EHD2 forms highly curved membrane scaffolds which stabilize a tubular membrane geometry with undulations along the tube’s axis, resembling caveolar neck architecture. As the researchers have now discovered, the first 19 amino acids act as a spacer. They ensure that only one chain at a time wraps around the neck of the caveolae. “Without it, multiple chains align side by side, causing the caveolae to lose their typical shape and function,” says the author.
And without functioning EHD2 chains, the bottlenecks become increasingly thinner and longer and eventually detach from the cell membrane.Moreover, in endothelial cells lacking EHD2, caveolar necks become narrower and more elongated.
“This study was technically very challenging. But it helps us understand how proteins come together to perform a specific task within the cell — in other words, how molecular functions become cellular functions,” the author adds.
Next, the scientists will try to visualize the EHD2 chains in living cells — precisely at the neck of a caveola. “If we succeed, we’ll also examine the protein chains in cells with altered caveola function. Then we might better understand the resulting diseases,” the author says.
There are many such diseases: In addition to lipid metabolism disorders, defective caveolae can cause diseases of the muscles, blood vessels, heart, lungs, and kidneys. “Without these invaginations, cells are less able to withstand mechanical stress. They’re also less able to regulate signaling processes,” explains the author. “That’s why tissues such as muscles, the heart, and blood vessels — which are constantly exposed to stress — are particularly vulnerable.”
