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Key heart and Alzheimer's disease protein imaged for first time in native state

Researchers for the first time have created a three-dimensional image of apolipoprotein E, a protein long associated with cardiovascular disease and more recently with Alzheimer's disease, as it appears when it is bound to fat-like substances known as lipids.

Using the technique known as x-ray crystallography, scientists at the Gladstone Institute of Cardiovascular Disease (GICD) have created the highest-resolution x-ray structure of a lipoprotein particle to date.

The work focuses apoE4, one of three specific forms of apolipoprotein E, commonly known as apoE. The breakthrough has already answered long-standing questions about the configuration of apoE4 in its active, or native, state. A complete understanding of the protein's functioning will be a key factor for development of future therapeutic interventions, according to the researchers.

Details of the works are reported in the January 13 edition of the Journal of Biological Chemistry.

"This is the first successful use of x-ray crystallography to reveal the structure of a protein bound to lipids," explains senior author Karl Weisgraber, PhD, a senior investigator at both GICD and the Gladstone Institute of Neurological Disease (GIND). "It's crucial to understand this molecule, since it plays such a pivotal role in both cardiovascular and neurological disease.

X-ray crystallography is a technique for determining the three-dimensional structure of a molecule by analyzing the x-ray diffraction patterns of crystals that make up the molecule.

"The next step is higher resolution, going from the current 10 angstroms to 3.5 or better," adds Weisgraber, who is also a professor of pathology at the University of California, San Francisco.

Lipid-bound proteins change their shape once they've bound to a lipid and have begun their key functions. "Until now, we've only been able to model the lipid-free structures of these proteins, and now we can begin learning about
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Source:Gladstone Institutes


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