Biologists at Argonne National Laboratory (ANL) have engineered and patented a bacterial factory that enables the study of membrane proteins. These proteins are challenging to study, but critical to understand because they represent 60 percent of drug targets. Studies of membrane proteins could lead to new and improved pharmaceutical treatments for a broad range of illnesses such as depression, heart disease, addictions and cystic fibrosis. Membrane proteins perform essential processes in the cell, such as controlling the flow of information and materials between cells, and mediating activities like nerve impulses and hormone action. These proteins are located in the rugged, oily, two-layered membrane that holds the cell together. One-third of the genome of any organism encodes membrane proteins. Biologists use 3-D images of proteins to better understand how they work. In drug design, for instance, the 3-D images help researchers develop a drug that specifically blocks the binding of a biological attacker that would cause disease. Researchers in ANL’s Biosciences Division are world leaders in automating the many steps it takes to determine 3-D protein structures, and have cut time and costs doing it. The structures of thousands of proteins are now known. Researchers studying water-soluble proteins often use commercial E. coli-based systems to express, or produce, copies of the protein. When membrane proteins are produced in E. coli, they overload the cell's bi-layers and cause the cells to die. The sources that have yielded the majority of the few known membrane-protein structures are organisms in which the target membrane protein is naturally abundant. Researchers took advantage of the natural characteristics of the Rhodobacter species of photosynthetic bacteria they were working with in another project. Under certain conditions—namely, in response to light or oxygen—Rhodobacter naturally produces large quantities of internal membranes. The biologists developed a system that successfully expresses hundreds of copies of a chosen membrane protein in Rhodobacter while simultaneously synthesizing the internal membranes in which they want to live. So far the team has cloned about 500 genes into Rhodobacter. First, they produced a variety of membrane proteins of different sizes, functions and physical properties, and have had a 60 percent success rate with them. As they continue to manufacture different membrane proteins, the team is tackling the next step to creating a pathway to protein crystallization for membrane proteins by developing specialized molecules, or reagents. ANL researchers are working with a multidisciplinary team from the University of Wisconsin-Madison, the University of Illinois-Chicago, and deCODE biostructures, Inc. of Bainbridge Island, Washington. They will focus on three types of reagents:
Researchers will test the reagents on the membrane proteins produced in the Rhodobacter ‘factory.' Funding for this research has been provided by the National Institute of Health's National Institute of General Medical Sciences, which recently granted the biologists a 5-year, $5 million research grant to continue their pursuit of a process leading to 3-D structures of membrane proteins. For more information, contact Evelyn Brown, 630-252-5510, or ebrown@anl.gov
|
