Breakthrough in Heart Disease Research: Scientists Unveil Structure of Key Cholesterol Protein

Study unlocks structural secrets of ApoB100 protein linked to heart disease

University of Missouri-ColumbiaFeb 3 2025 Low-density lipoproteins (LDL) - commonly known as bad cholesterol - have long been on scientists' radar as a major contributor to heart disease. But these microscopic troublemakers have hidden their inner workings behind a maze of complexity. That is, until now. In a new study published in Nature, University of Missouri researchers have, for the first time, revealed the specific shape and structure of one of the body's most important yet complicated proteins: ApoB100. Acting as a kind of molecular exoskeleton, this protein wraps around LDL particles, allowing them to travel through the bloodstream, researchers found. The discovery may one day lead to the design of new drugs that target LDL, providing more precise treatments for high cholesterol and heart disease and potentially reducing the side effects of widely prescribed medications such as statin drugs. Major tools for a microscopic protein Researchers Zachary Berndsen and Keith Cassidy were recruited to Mizzou because of their knowledge of cryo-electron microscopy, a technique that uses electrons to determine the 3D structure of biological molecules. That expertise, combined with significant infrastructure investments at Mizzou - particularly in the Electron Microscopy Core at the Roy Blunt NextGen Precision Health building - made their latest finding possible. These cryo-electron microscopes allow us to see things at a much higher resolution than the traditional microscopes familiar to most of us. Instead of just seeing a cell's shape, for instance, these tools allow us to now see what individual proteins are shaped like, which are thousands of times smaller than a typical cell, and that is how we made our recent discovery. What this technology means for scientific advancement is incredible, and we are thankful Mizzou invested in both us and our research." Zachary Berndsen, assistant professor, MU School of Medicine After Berndsen, a biochemist, used the nearly two-story tall cryo-electron microscope to discover how ApoB100 was structured, his co-author, Cassidy, a physicist in the College of Arts and Science, painted an even more detailed picture of the protein using a combination of artificial intelligence and Mizzou's collection of high-powered supercomputers called Hellbender, which allows researchers to process huge amounts of data at record speeds. "We often think of cholesterol as purely bad, but in general it is actually a very useful and beneficial molecule involved in numerous important processes throughout the body, such as building hormones and maintaining cell membrane fluidity," Cassidy, an assistant professor of biological physics, said. "By integrating an AI neural network called AlphaFold with the cryo-electron microscopy images, we were able to get an even more detailed and higher-resolution picture of the structure of ApoB100. Ideally, this can lead to more targeted treatments that reduce heart disease-related risks without interfering with all the benefits cholesterol brings throughout the body." Basic science, big-picture impact The discovery not only helps researchers better understand fundamental aspects of fat and cholesterol metabolism, but it could also lead to the development of better, more specific testing and treatment for "bad" cholesterol, Berndsen said. "The most common ways of testing for cholesterol levels are currently not very specific," he said. "Going forward, if we can test for how many copies of this ApoB100 are in your blood, that would be a more accurate indicator of risk for heart disease." Both Berndsen and Cassidy have a family history of heart disease - the leading cause of death worldwide - so their research is personal. "We are trying to bridge the gap between the basic science we are doing now and the applied health benefits down the road," Berndsen said. "Our work can help benefit the health of the general public, so it is very rewarding to do what we do." "The structure of apolipoprotein B100 from human low-density lipoprotein" was published in Nature. University of Missouri-Columbia Journal reference: Berndsen, Z. T., & Cassidy, C. K. (2024). The structure of apolipoprotein B100 from human low-density lipoprotein. Nature. doi.org/10.1038/s41586-024-08467-w.

A protein at the heart of heart disease

Low-density lipoproteins (LDL) -- commonly known as bad cholesterol -- have long been on scientists' radar as a major contributor to heart disease. But these microscopic troublemakers have hidden their inner workings behind a maze of complexity. That is, until now. In a new study published in Nature, University of Missouri researchers have, for the first time, revealed the specific shape and structure of one of the body's most important yet complicated proteins: ApoB100. Acting as a kind of molecular exoskeleton, this protein wraps around LDL particles, allowing them to travel through the bloodstream, researchers found. The discovery may one day lead to the design of new drugs that target LDL, providing more precise treatments for high cholesterol and heart disease and potentially reducing the side effects of widely prescribed medications such as statin drugs. Major tools for a microscopic protein Researchers Zachary Berndsen and Keith Cassidy were recruited to Mizzou because of their knowledge of cryo-electron microscopy, a technique that uses electrons to determine the 3D structure of biological molecules. That expertise, combined with significant infrastructure investments at Mizzou -- particularly in the Electron Microscopy Core at the Roy Blunt NextGen Precision Health building -- made their latest finding possible. "These cryo-electron microscopes allow us to see things at a much higher resolution than the traditional microscopes familiar to most of us," said Berndsen, an assistant professor in the MU School of Medicine. "Instead of just seeing a cell's shape, for instance, these tools allow us to now see what individual proteins are shaped like, which are thousands of times smaller than a typical cell, and that is how we made our recent discovery. What this technology means for scientific advancement is incredible, and we are thankful Mizzou invested in both us and our research." After Berndsen, a biochemist, used the nearly two-story tall cryo-electron microscope to discover how ApoB100 was structured, his co-author, Cassidy, a physicist in the College of Arts and Science, painted an even more detailed picture of the protein using a combination of artificial intelligence and Mizzou's collection of high-powered supercomputers called Hellbender, which allows researchers to process huge amounts of data at record speeds. "We often think of cholesterol as purely bad, but in general it is actually a very useful and beneficial molecule involved in numerous important processes throughout the body, such as building hormones and maintaining cell membrane fluidity," Cassidy, an assistant professor of biological physics, said. "By integrating an AI neural network called AlphaFold with the cryo-electron microscopy images, we were able to get an even more detailed and higher-resolution picture of the structure of ApoB100. Ideally, this can lead to more targeted treatments that reduce heart disease-related risks without interfering with all the benefits cholesterol brings throughout the body." Basic science, big-picture impact The discovery not only helps researchers better understand fundamental aspects of fat and cholesterol metabolism, but it could also lead to the development of better, more specific testing and treatment for "bad" cholesterol, Berndsen said. "The most common ways of testing for cholesterol levels are currently not very specific," he said. "Going forward, if we can test for how many copies of this ApoB100 are in your blood, that would be a more accurate indicator of risk for heart disease." Both Berndsen and Cassidy have a family history of heart disease -- the leading cause of death worldwide -- so their research is personal. "We are trying to bridge the gap between the basic science we are doing now and the applied health benefits down the road," Berndsen said. "Our work can help benefit the health of the general public, so it is very rewarding to do what we do."