How a protein disrupts cholesterol regulation

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Washington, February 5 : Scientists have uncovered the specific way by which a destructive protein destroys a molecule that removes "bad" cholesterol from the blood.

"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," said Dr. Jay Horton, professor of internal medicine and molecular genetics and a senior author of the study, which appears online this week in the Proceedings of the National Academy of Sciences. He says that the PCSK9 protein disrupts the activity of the low-density lipoprotein receptor (LDLR), a key molecule that latches on to latches on to "bad" cholesterol in the bloodstream and removes it by drawing it into the cells.

According to him, the PCSK9 protein latch on to the LDL receptor, and thereby triggers a chain of biochemical reactions that leads to the destruction of the receptor. With fewer receptors available, more "bad" cholesterol remains in the bloodstream, says the researcher.

"You want to have LDL receptors to clear LDL from the blood - that's a good thing. So you don't want to have PCSK9; it normally functions in a harmful way," Dr. Horton said.

The researchers used X-rays bounced off crystals made up of both PCSK9 and a portion of the LDLR protein in their study, and identified small regions of each protein that attach to each other. Thereafter, they created a detailed structural model of the area.

"It looks like those portions are absolutely essential for the interaction to take place," Dr. Horton said.

The researchers are now designing antibodies and small chains of peptides, the building blocks of proteins, which have the ability to jam the interaction between LDLR and PCSK9.

While statin drugs work by increasing the number of LDL receptors on cells, the researchers believe that a drug targeting PCSK9 may prevent the existing receptors from being degraded.

"These studies suggest that inhibiting PCSK9's action may be another route to lowering LDL cholesterol in individuals with high cholesterol," said Dr. Horton.

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