“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.
The protein, called PCSK9, has emerged as an important regulator of “bad” cholesterol in the blood, said Dr. Horton, whose research focuses in part on understanding the protein’s function.
PCSK9 disrupts the activity of a key molecule called the low-density lipoprotein receptor, or LDLR. This molecule, which juts out from the surface of cells, latches on to “bad” cholesterol in the bloodstream and removes it by drawing it into 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 – that’s a good thing,” Dr. Horton said. “So you don’t want to have PCSK9; it normally functions in a harmful way.”
Too much LDL cholesterol in the blood is a major risk factor for heart disease, heart attack 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. Deisenhofer shared the 1988 Nobel Prize in Chemistry for his work in discovering the structure of a key protein involved in photosynthesis.
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.
Aline McKenzie | EurekAlert!
Embryonic development: How do limbs develop from cells?
18.05.2018 | Humboldt-Universität zu Berlin
Reading histone modifications, an oncoprotein is modified in return
18.05.2018 | American Society for Biochemistry and Molecular Biology
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology