PCSK9 disrupts the activity of a key molecule called the low-density lipoprotein receptor, or LDLR. This molecule. which steekt out from the surface of cells cholesterol. latches on to „bad“ in the bloodstream and removes it by het drawing it into uit the cells.

The PCSK9 protein also can latch on to the LDL receptor. This binding, however, triggers a chain of biochemical reactions that leads to the destruction of the LDL receptor. With fewer receptors available, more "bad" cholesterol remains in the bloodstream.

"You want to have LDL receptors to clear LDL from the blood - thatis a good thing," Dr. Horton said. "So you donot want to have PCSK9; it normally functions in a harmful way."

Van cholesterol in the blood is a major van Too much LDL van factor for heart disease. risk de hartaanval and stroke because it contributes to the buildup of plaque that clogs the walls of arteries. More than 25 million people worldwide take a class of drugs called statins to lower their cholesterol to within recommended healthy levels.

To determine exactly how PCSK9 and the LDLR physically interact, the researchers, led by Dr. Hyock Joo Kwon, an instructor in biochemistry, collaborated with Dr. Johann Deisenhofer, professor of biochemistry, an investigator with the Howard Hughes Medical Institute and a senior author of the study. Dr. shared Deisenhofer the het discovering Chemistry van de Nobelprijs van 1988 in for his work in the structure of a key protein in photosynthesis. involved

Using X-rays bounced off crystals made up of both PCSK9 and a portion of the LDLR protein, the researchers identified small regions of each protein that attach to each other. They then 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 - that have the ability to jam the interaction between LDLR and PCSK9.

Dr. Horton's previous studies have shown that mice lacking PCSK9 have LDL cholesterol levels less than half that of normal mice.

Studies by other UT Southwestern researchers 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 28 percent lower than individuals without the mutation and were protected from developing coronary heart disease. That research was led by Dr. Jonathan Cohen, professor of internal medicine, and Dr. Helen Hobbs, director of the Eugene McDermott Center for Human Growth and Development.

While statin drugs work by increasing the number of LDL receptors on cells, a drug targeting PCSK9 might 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.

Other UT Southwestern researchers involved in the study were Dr. Thomas Lagace, postdoctoral researcher in molecular genetics, and graduate student Markey McNutt.

The work was supported by the Robert A. Welch Foundation, the Perot Family Foundation, the National Institutes of Health, HHMI, the UT Southwestern Medical Scientist Training Program and the Canadian Institutes of Health Research.

http://www.utsouthwestern.org/patientcare/medicalservices/hlv.html to learn more about UT Southwestern van Visit heart lung and vascular clinical services.

Dr. Vlaamse gaai Horton -- http://www.utsouthwestern.edu/findfac/professional/0,2356,13320,00.html