Researchers at National Jewish Medical and Research Center who are studying a protein implicated in the development of rheumatoid arthritis and lupus, have discovered a unique “flap” that is crucial to the protein’s function. These findings provide unique insight into an important immune-system protein, and suggest that the flap-free version may one day serve as a treatment for autoimmune disease.
The study, published in the February 8 issue of Cell, states the molecule, known as Tall-1, has generated intense interest in the biomedical community because of its role in both autoimmunity and the normal immune response.
“Our studies have revealed the structural element crucial to Tall-1’s ability to trigger maturation of B cells [an autoimmune cell] and antibody production,” said Gongyi Zhang, Ph.D., Assistant Professor of Immunology at National Jewish. “By removing Tall-1’s unique flap, we have created a molecule that could have important therapeutic applications in lupus, rheumatoid arthritis, and other autoimmune diseases.”
Tall-1 is an important regulator of the immune system. It spurs B cells to mature and produce antibodies, one of the body’s major defense mechanisms. People with lupus and rheumatoid arthritis have been shown to have high levels of Tall-1 in their blood.
Hong-Bing Shu, Ph.D., Assistant Professor of Immunology at National Jewish, originally identified Tall-1 in 1999 and soon thereafter one of its receptors, BCMA. He collaborated with Dr. Zhang to determine the protein’s unique shape. Tall-1 has a flap, which consists of a loop of eight amino acids not found in related proteins in the tumor necrosis factor (TNF) family. While other TNF family members cluster into units of three molecules, Tall-1 clusters into a much larger, 60-molecule ball, which appears crucial to the protein’s biological activity.
Dr. Zhang’s analysis indicated that the flap is responsible for this unique clustering. When the researchers created a modified version of Tall-1 lacking the flap, it failed to assemble into the 60-molecule ball. It also failed to stimulate B cells, even though the modified Tall-1 did bind to one of its target receptors, BCMA.
“The flap region is essential for the proper function of Tall-1 in cell cultures,” said Dr. Shu. “We believe this region is a good target for development of small molecule drugs against lupus, rheumatoid arthritis, and other disorders involving the immune system and B cells. We are also investigating whether the flap-less Tall-1 mutant can be used to compete with the normal Tall-1 in vivo and inhibit its activity.”