An illustration of vitronectin. Credit: Sanford Burnham Prebys/Francesca Marassi
Researchers have found vitronectin to be a promising target for macular degeneration.
Francesca Marassi, Ph.D., a professor at Sanford Burnham Prebys, is leading research that sheds light on the molecular mechanisms behind macular degeneration, which accounts for more than 90% of all eye-related vision loss. age. The flexible structure of a key blood protein implicated in macular degeneration and other age-related disorders, such as Alzheimer’s and atherosclerosis, is described in the research, which was published in the Biophysical Journal.
Francesca Marassi, Ph.D. Credit: Sanford Burnham Prebys
“Proteins in the blood are under constant and changing pressure due to the different ways blood flows through the body,” says Marassi. “For example, blood flows more slowly through the small blood vessels in the eyes than through the larger arteries around the heart. Blood proteins must be able to respond to these changes, and this study gives us fundamental truths about how they adapt to their environment, which is essential for targeting these proteins for future treatments.
Our blood contains hundreds of proteins, but the researchers focused on vitronectin because it’s one of the most common. In addition to being present in the blood in large quantities, vitronectin is a crucial component of cholesterol and can be found in the scaffolding between cells.
Vitronectin has been implicated in many age-related disorders, but the most promising target for Marassi’s team is macular degeneration, which affects up to 11 million individuals in the United States. By 2050, this number is expected to double.
“This protein is an important target for macular degeneration because it accumulates in the back of the eye, causing vision loss. Similar deposits appear in the brain in Alzheimer’s disease and in the arteries in atherosclerosis,” says Marassi. “We want to understand why this happens and use this knowledge to develop new treatments.”
In order to answer this question, the researchers were curious to find out how the structure of the protein changed under various pressures and temperatures, simulating the conditions observed in the human body.
“Determining the structure of a protein is the most important part of determining its function,” adds Marassi.
Through detailed biochemical analysis, the researchers discovered that the protein can subtly change shape under pressure. These changes cause it to bind more readily to calcium ions in the blood, which researchers say leads to the buildup of calcified plaque deposits characteristic of macular degeneration and other age-related diseases.
“It’s a very subtle rearrangement of the molecular structure, but it has a big impact on how the protein works,” says Marassi. “The more we learn about the protein at the structural and mechanistic level, the more likely we are to successfully target it with treatments.”
This structural knowledge will streamline the development of treatments for macular degeneration, as it will allow researchers and their partners in the biotech industry to design tailor-made antibodies that selectively block the protein’s calcium binding without disrupting its other important functions in the organism.
“It will take some time to convert it into a clinical treatment, but we hope to have a working antibody as a potential treatment in a few years,” says Marassi. “And since this protein is so abundant in the blood, there may be other exciting applications for this new knowledge that we don’t even know about yet.”
Reference: “Calcium-induced environmental adaptability of blood protein vitronectin” by Ye Tian, Kyungsoo Shin, Alexander E. Aleshin, Wonpil Im, and Francesca M. Marassi, September 2, 2022, Biophysical Journal.
DOI: 10.1016/j.bpj.2022.08.044
The study was funded by the National Institutes of Health, the National Science Foundation and the Canadian Institutes of Health Research.
