In a breakthrough powered by AlphaFold, scientists have mapped the structure of the massive protein that offers “bad cholesterol” its form – a discovery that might help transform how researchers and clinicians treat the world’s leading reason for death
The race to disclose a key protein behind heart disease has long been each a very important public health goal and a stubborn scientific problem.
For assistant professors Zachary Berndsen and Keith Cassidy on the University of Missouri (Mizzou), it was also personal. Each have a family history of heart disease – a reminder of what’s at stake of their work to raised understand and ultimately help treat this deadly condition.
“For 50 years, people have desired to see what this protein looked like,” says Berndsen.
That protein, apoB100, has defied mapping not only since it’s enormous (for a protein), but additionally since it connects to fats and other molecules in complicated ways. ApoB100 forms the molecular scaffold of “bad cholesterol”, which is thought to scientists as low-density lipoprotein (LDL).
LDL is the foremost carrier of fat through the bloodstream and a key risk factor for atherosclerotic heart problems (ASCVD), the world’s leading reason for death. Discovering the structure of its key protein promised to make clear how bad cholesterol becomes harmful contained in the body, giving scientists a greater probability to develop ways to forestall and treat ASCVD. AlphaFold is playing a central role on this effort.
At Mizzou, biochemist Berndsen first used cryo-electron microscopy (cryo-EM) to capture images of LDL particles. The photographs weren’t sharp enough to map the structure of apoB100 with atomic precision, so Berndsen’s physicist collaborator, Cassidy, turned to AlphaFold. He used it to generate atomic-resolution predictions of the protein’s structure after which refined those predicted shapes by comparing them against the cryo-EM image data.
Coming at the issue using each cryo-EM microscopy and Alphafold is what unlocked this breakthrough, says Cassidy: “AlphaFold played a profound role on this discovery, providing the raw material to interpret our experimental structure in a way that was frankly unimaginable before.”
The resulting model revealed bad cholesterol’s 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 within the bloodstream. Knowing this structure opens latest possibilities for stopping, diagnosing and treating high cholesterol and ASCVD, including therapies that might goal LDL more precisely. The potential profit to global health is difficult to overstate.
While such applications will take time, revealing the structure of apoB100 is a landmark achievement, and a deeply satisfying one for Berndsen. “It was the primary structure I ran through AlphaFold the week it became available, and the primary protein I wanted to take a look at with our two-storey cryo-EM machine,” he says. “Solving the structure of apoB100 was a dream come true.”
