Revealing a key protein behind heart disease

In a breakthrough powered by AlphaFold, scientists have mapped the structure of the large protein that gives âbad cholesterolâ its form â a discovery that could help transform how researchers and clinicians treat the worldâs 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 â a reminder of whatâs at stake in their work to better understand and ultimately help treat this deadly condition.

âFor 50 years, people have wanted to see what this protein looked like,â says Berndsen.

That protein, apoB100, has defied mapping not only because itâs enormous (for a protein), but also because it connects to fats and other molecules in complicated ways. ApoB100 forms the molecular scaffold of âbad cholesterolâ, 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 worldâs 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. The images werenât sharp enough to map the structure of apoB100 with atomic precision, so Berndsenâs physicist collaborator, Cassidy, turned to AlphaFold. He used it to generate atomic-resolution predictions of the proteinâs structure and then refined those predicted shapes by comparing them against the cryo-EM image data.

Coming at the problem using both cryo-EM microscopy and Alphafold is what unlocked this breakthrough, says Cassidy: âAlphaFold played a profound role in this discovery, providing the raw material to interpret our experimental structure in a way that was frankly impossible before.â

The resulting model revealed bad cholesterolâs key protein in remarkable detail: a cage-like shell that wraps around each LDL particle, including a ribbon-like belt that keeps the particle intact in the bloodstream. Knowing this structure opens new possibilities for preventing, diagnosing and treating high cholesterol and ASCVD, including therapies that could target LDL more precisely. The potential benefit to global health is hard to overstate.

While such applications will take time, revealing the structure of apoB100 is a landmark achievement, and a deeply satisfying one for Berndsen. âIt was the first structure I ran through AlphaFold the week it became available, and the first protein I wanted to look at with our two-storey cryo-EM machine,â he says. âSolving the structure of apoB100 was a dream come true.â