In a breakthrough powered by AlphaFold, scientists have mapped the structure of the large protein that gives “bad cholesterol” its form – a discovery that could help transform how researchers and clinicians treat the world’s leading cause of death

The race to reveal a key protein behind heart disease has long been both an important public health goal and a stubborn scientific problem.

For assistant professors Zachary Berndsen and Keith Cassidy at the University of Missouri (Mizzou), it was also personal. Both have a family history of heart disease – a reminder of what’s at stake in their work to better understand and ultimately help treat this deadly condition.

“For 50 years, people have wanted to see what this protein looked like,” says Berndsen.

That protein, apoB100, has defied mapping not only because it’s enormous (for a protein), but also because it connects to fats and other molecules in complicated ways. ApoB100 forms the molecular scaffold of “bad cholesterol”, which is known to scientists as low-density lipoprotein (LDL).

LDL is the major carrier of fat through the bloodstream and a key risk factor for atherosclerotic cardiovascular disease (ASCVD), the world’s leading cause of death. Discovering the structure of its key protein promised to shed light on how bad cholesterol becomes harmful inside the body, giving scientists a better chance to develop ways to prevent and treat ASCVD. AlphaFold is playing a central role in this effort.

At Mizzou, biochemist Berndsen first used cryo-electron microscopy (cryo-EM) to capture images of LDL particles.

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