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US researchers have discovered exactly how a destructive protein binds to and interferes with one of the molecules involved in removing low-density lipoproteins (LDL), the so-called "bad" cholesterol, from the blood plasma. Jay Horton, professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center, and colleagues Thomas Lagace and Markey McNutt, suggest that their findings based on X-ray structural studies of the protein, PCSK9, could lead to a new approach to managing cholesterol levels. "The practical benefit of this finding is that we can now search for new ways to lower cholesterol by designing targeted antibodies to disrupt this interaction," explains Horton. In 2003, Catherine Boileau of the Hôum;pital Necker-Enfants Malades in Paris and colleagues mapped a region on human chromosome 1 that seemed to be linked to hypercholesterolemia in French families. In a 41-gene region on this chromosome those researchers identified PCSK9 as a candidate gene. PCSK9 (originally called Narc-1) is a member of the proprotein convertase family of proteases and has emerged as one of the most important regulators of so-called "bad" cholesterol in the blood. The protein is expressed in the liver and neuronal tissue as well as in kidney mesenchymal cells and intestinal epithelia. The PCSK9 gene is itself controlled by sterols, of which cholesterol is one of many, indeed, dietary cholesterol potently suppresses its expression. Horton and his colleagues have focused on this molecule with a view to understanding the role it plays in modulating bad cholesterol. PCSK9 is known to disrupt the activity of another compound, the low-density lipoprotein receptor, or LDLR. LDLR is present on the surface of cells and sequesters bad cholesterol from the bloodstream withdrawing it into the cells' interior. PCSK9 itself can become attached to LDLR too and this triggers a chain of biochemical reactions that leads to the destruction of the LDL receptor. The end result is that with fewer functioning receptors on the surface of cells, the bad cholesterol is not sequestered from the bloodstream at such a high rate and "cholesterol levels" rise. Raised LDL cholesterol levels in the blood is usually considered to be a major risk factor for cardiovascular disease and the problems it causes, such as heart attacks and stroke. Its presence contributes to the accumulation of fatty plaques that clog the walls of arteries. "You want to have LDL receptors to clear LDL from the blood - that's a good thing," Horton explains, "So you don't want to have PCSK9; it normally functions in a harmful way." Horton's previous studies have shown that mice lacking PCSK9 have LDL cholesterol levels less than half that of normal mice. To determine exactly how PCSK9 and the LDLR interact physically, Horton and colleagues Hyock Joo Kwon together with Johann Deisenhofer of the Howard Hughes Medical Institute used crystallography to determine which regions of PCSK9 and a portion of the LDLR protein (EGF-A) can complex to each other. In related work at UT Southwestern, Jonathan Cohen, Helen Hobbs, and their colleagues have found that people with mutations in the PCSK9 gene, which prevented them from making normal levels of the PCSK9 protein, had LDL cholesterol levels almost a third lower than individuals without the mutation and were apparently protected from developing coronary heart disease. The findings provide additional evidence of the role of PCSK9 in cholesterol modulation. These studies suggest that inhibiting PCSK9's action may provide an alternative to statins for lowering LDL cholesterol in individuals with high cholesterol, says Horton. Having built their model, the researchers are now designing antibodies and small chain peptides to block this interaction. A drug targeting PCSK9 might prevent the existing LDLR receptors from being degraded. Related links:
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