Lipoprotein structure gives insights into “bad” cholesterol

A model of the structure of apoB100, the main component of low-density lipoprotein, or LDL.Reimund et al., Nature

Cholesterol is a waxy, fat-like substance found in all the body’s cells. It’s needed for many body functions. Cholesterol is transported through the bloodstream in structures called lipoproteins. One of these structures is called low-density lipoprotein, or LDL. Researchers have long known that excess LDL cholesterol, or “bad cholesterol,” can lead to a buildup of fatty deposits in arteries, which raises the risk for heart attack or stroke.

Scientists haven’t had a detailed understanding of how LDL binds to its receptor molecule. The binding helps LDL leave the bloodstream and move into cells, where cholesterol can be removed. Major obstacles to visualizing this binding have been the association of LDL with lipids like cholesterol and the large size of LDL’s main structural component, a protein called apolipoprotein B100.

To learn more, a team of NIH researchers turned to an imaging technique called cryo-electron microscopy, or cryo-EM. This method let them visualize the interaction between the apoB100 protein and the LDL receptor in unprecedented detail, without the need for structure-altering dyes or crystallization used in other high-resolution techniques.

The scientists used protein prediction software based on artificial intelligence to examine different views and further refine their structures. The team was led by Dr. Alan Remaley of NIH’s National Heart, Lung, and Blood Institute and Dr. Joseph Marcotrigiano of NIH’s National Institute of Allergy and Infectious Diseases. Their results appeared in Nature on December 11, 2024.

The structural visualization showed that apoB100 binds to the LDL receptor at two different locations. Both interfaces are important for receptor binding.

The researchers also examined the effects of genetic mutations known to interfere with cholesterol clearance. They found that many mutations associated with a rare inherited condition called familial hypercholesterolemia mapped to the interface between apoB100 and the LDL receptor. People with this condition have dangerously high levels of LDL cholesterol beginning at birth. This raises their risk for heart attack at a very young age. The scientists found that variants associated with familial hypercholesterolemia tended to cluster in particular regions of the apoB100 protein.

The scientists note that increased understanding of the binding between the LDL structural protein and its receptor might lead to more highly targeted drugs for reducing blood cholesterol.

“LDL is one of the main drivers of cardiovascular disease, which kills one person every 33 seconds,” Remaley says. “If you want to understand your enemy, you want to know what it looks like.”

“LDL is enormous and varies in size, making it very complex. No one’s ever gotten to the resolution we have,” adds Marcotrigiano. “We could see so much detail and start to tease apart how it works in the body.”