Secreted Protein Degrades LDL Receptors and Elevates Serum Cholesterol Levels

A secreted protein called PCSK9 (proprotein convertase subtilisin/kexin type 9) modulates LDL (low density lipoprotein) metabolism by binding to and degrading cellular LDL receptors (LDLR).

Previous studies had shown that that individuals with mutations in the PCSK9 gene, which prevented them from making normal levels of the PCSK9 protein, had LDL cholesterol levels 28% lower than those without the mutation and were protected from developing coronary heart disease. On the other hand, a mutation that increased PCSK9 binding to LDLR was found to cause hypercholesterolemia due to excessive degradation of the receptor that resulted in extremely high cholesterol levels.

In the current study investigators at the University of Texas Southwestern Medical Center (Dallas, USA) sought to determine how PCSK9 functions on the molecular level.

They reported in the April 17, 2009, online edition of the Journal of Biological Chemistry (JBC) that peptide fragments of PCSK9 were able to prevent the whole protein from binding to LDLR in cell cultures. This evidence suggested that PCSK9 functioned as an extracellular factor and was not an intrinsic cellular protein.

"The fact that it works mostly extracellularly provides more opportunities to develop different kinds of therapies," said contributing author Dr. Jay Horton, professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center. "It is much easier to design inhibitors of PCSK9 function to work outside a cell than to develop a small molecule that works inside a cell. Therefore, approaches to block the protein's activity in the blood should be successful in reducing plasma cholesterol levels. Our work paves the way for a more active pursuit of antibody and peptide approaches to block the destructive actions of PCSK9."

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University of Texas Southwestern Medical Center