Key heart and Alzheimer's disease protein imaged for first time
in native state
January 16, 2006
Laptop Battery 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.
Consuming plenty of onions may be one key way to help guard against cancer and heart disease—the two leading causes of death in the United States.
Thinkpad 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.
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Microsoft 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.
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Laptop Computers Details of the works are reported in the January 13 edition of
the Journal of Biological Chemistry.
Coronary artery disease (CAD) is the single deadliest disease in the United States. An estimated 13.2 million people have CAD, or 6.4 percent of the population (American Heart Association 2004). An estimated 700, 000 people in the United States will have their first heart attack this year. Another half a million will have another heart attack (American Heart Association 2004).
Laptop Computer "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.
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Desktop Computer 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.
Notebooks "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.
Lenovo 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 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."
Hard Drive ApoE, and particularly apoE4, has long been studied for its role
as a lipid transport protein and its involvement in cardiovascular
disease. Much of the pioneering work on this molecule has been done
at Gladstone since the institutes' founding in 1979, led by
researchers, including Weisgraber, who had been studying the
protein at the National Institutes of Health before transitioning
to Gladstone.
Travelstar In the late 1980s, apoE emerged as a major player in
neurological disease, based in part on observations made at
Gladstone. Next to one's age, the greatest known risk factor for
Alzheimer's disease is the gene for apoE4. ApoE4 is associated with
40-60 percent of cases of sporadic and familial Alzheimer's.
Gateway 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.
Laptop Parts "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.\\\
Software Gladstone Institutes
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