Enzyme that Degrades LDL Receptors Is Target for Cholesterol Reducing Therapy

Binding of PCSK9 to liver cell LDL receptors, results in degradation of the receptors and decline in the liver's ability to remove LDL from circulation. Individuals with mutations in the PCSK9 gene that prevent them from producing normal levels of the PCSK9 protein have LDL cholesterol levels 28% lower than those without the mutation and are protected from developing coronary heart disease. Furthermore, mice that have been genetically engineered to lack the PCSK9 gene have LDL cholesterol levels less than half that of normal mice.

The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDL receptor. Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) used sophisticated X-ray crystallography techniques to study the interaction between PCSK9 and LDL receptors.

They reported in the February 4, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS) that the binding site for the LDL receptor EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374–Tyr) increases the affinity of PCSK9 toward the LDL receptor and increases plasma LDL-cholesterol (LDL-C) levels in humans.

"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,” explained Dr. Jay Horton, professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center. "These studies suggest that inhibiting PCSK9's action may be another route to lowering LDL cholesterol in individuals with high cholesterol. You want to have LDL receptors to clear LDL from the blood – that is a good thing. So you do not want to have PCSK9; it normally functions in a harmful way.”


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University of Texas Southwestern Medical Center