Researchers for the first time have created a three-dimensional image of apolipoprotein E, a protein long associated with cardiovascular disease and 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 on apoE4, one of three specific forms of apolipoprotein E, commonly known as apoE.
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."
"The next step is higher resolution, going from the current 10 angstroms to 3.5 or better," adds Weisgraber, professor of pathology at the University of California, San Francisco.
"Until now, we've only been able to model the lipid-free structures of these proteins, and now we can begin learning about their lipid-bound forms," says lead author Clare Peters-Libeu, a GICD and GIND research scientist. "It's a huge step forward for those of us involved in the field."
Everyone inherits two copies, or alleles, of every gene, one from each parent, Weisgraber explains.
As the number of apoE4 alleles increases from 0 to 2, the risk of AD increases from 20 to 90 percent, and the typical age of onset decreases from 84 years to 68 years.
The presence of one apoE4 allele results in an estimated 45 percent chance of developing Alzheimer's by 85 years of age. With two apoE4 alleles, the risk increases to 50–90 percent.
"Insights into the basic biology of apoE-and particularly apoE4-gained by Gladstone scientists have been invaluable in the study of Alzheimer's disease," says Peters-Libeu.
"Gaining a complete, three-dimensional understanding of its configuration in its native, lipid-bound state will inevitably lead to even more insights into its role in cardiovascular and neurological disease in the years to come."