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While cholesterol is required for normal health, too much of it can be deadly. Along with high blood pressure and cigarette smoking, it is one of the three major risk factors for heart disease. More than half of all adult Americans have a blood cholesterol level that is higher than 'desirable.'
The problem with too much blood cholesterol is that over time it can build up in the walls of your arteries (a process called atherosclerosis) and can slow or block the flow of blood to your heart. Among many things, blood carries a constant supply of oxygen to the heart. Without oxygen, heart muscle weakens, resulting in chest pain, heart attacks, or even death. There are two types of cholesterol - 'good' and 'bad'. Actually these descriptions refer to the lipoproteins that carry cholesterol throughout the body. 'Good' cholesterol is associated with high density lipoproteins (HDLs) that remove excess cholesterol from the body by transporting it to the liver where it is disposed of. 'Bad' cholesterol is associated with low density lipoproteins (LDLs). Getting cholesterol into cells requires the LDL receptor. Normally, the LDL receptor keeps the cholesterol level in balance. If the receptor malfunctions then cholesterol levels can skyrocket. While most of us can control our blood cholesterol levels by following a diet that is low in saturated fat and cholesterol, a small percentage of people cannot. About 7 out of 1000 people suffer from familial hypercholesterolemia (FH). FH is an inherited genetic disease that is marked by high cholesterol levels and an increased risk of heart disease. Currently, there are more than 600 mutations in the LDL receptor gene that give rise to FH. The LDL receptor consists of several parts or domains that must form and interact properly to function. One region of the receptor is crucial for the release of bound LDL. By solving the X-ray crystal structure of this part of the LDL receptor, Blacklow and colleagues at Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, have gained a more detailed understanding of how mutations in this part of the receptor lead to disease (Nature Structural Biology, Vol. 8, No. 6, 01 Jun 2001). They find that many of the mutations seem to affect either the folding of the individual domains within this part of the receptor or the interaction between these domains. These studies are an important step in understanding how the LDL receptor functions normally as well as how mutations in the receptor cause it to go awry. Joachim Herz at the University of Texas Southwestern Medical Center, Dallas, Texas, USA, discusses these findings in an accompanying News and Views report. Contact: Dr. Stephen C. Blacklow
Brigham and Women's Hospital and Harvard Medical School
Department of Pathology
75 Francis Street
Boston, Massachusetts 02115
USA
Telephone: 617 732 5799
Fax: 617 264 5296
Email: sblacklow@rics.bwh.harvard.edu Dr. Joachim Herz
University of Texas Southwestern Medical Center
Department of Biophysics & Molecular Genetics
5323 Harry Hines Blvd.
Dallas, Texas
USA
Telephone: 214-648-5633
Fax: 214-648-8804
Email: herz@utsw.swmed.edu (C) Nature Structural Biology press release.
Message posted by: Trevor M. D'Souza
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