a7 protein ready for close-up

Dallas-March 17, 2021-UT Southwestern researchers have identified the structure of a key member of the protein family called the nicotinic acetylcholine receptor in three different forms. Published online today on Cell, the study could lead to new drug treatments for a variety of diseases and infectious diseases, including schizophrenia, lung cancer, and even COVID-19.

Nicotinic acetylcholine receptors act as ion channels on the cell surface and are members of a broader superfamily of proteins called Cys loop receptors found on many cell-type membranes. When the appropriate molecules settle on these receptors, gate channels open and ions spill from the outside to the inside of the cell, triggering other cellular processes. Nicotinic acetylcholine receptors respond to acetylcholine, a molecule used by nerve cells to communicate with each other. However, it also reacts with other molecules outside the body, such as nicotine, the essential nutrient choline, and a toxin called epibatidine in the skin of poison dart frogs.

These receptors, identified in nerves, lungs, and immune cells, are associated with conditions such as psychiatric disorders, neurodegenerative disorders, lung cancer, and the destructive immune response characteristic of COVID-19 and other infectious diseases. doing.

The researcher had Previously identified Structure of some members of the Cys loop superfamily. It is an important step in creating a drug that adapts to these ion channels and blocks or enhances function.However, research leaders Colleen M. Noviello, Ph.D., senior researchers at UTSW, and Ryan E. Hibbs, Ph.D., Associate Professor of Neuroscience and Biophysics at UTSW, the shape or conformation of these channels is not fixed. Cys loop receptors circulate in three major states during the corresponding gating cycle as they close and wait for a ligand or activating molecule (resting state) to respond. When they respond to the ligand and open for ion flow (open state); or when they still retain the ligand but close again (desensitized state).

After years of striving to characterize the structure of a major nicotinic acetylcholine receptor called a7, Noviello and Hibbs gained significant boost in 2016 after UTSW. Purchased equipment For cryo-electron microscopy or cryo-EM. This technology allows scientists to take pictures of biological molecules at atomic resolution. When researchers and their colleagues added a chaperone protein (a protein that helps support and protect other proteins) to a7, it helped a7 maintain its proper shape.

Using these new tools, researchers have imaged the a7 in various conformations. Because the structure of a7 is dynamic and can shift and sway, researchers have added various ligands to stabilize it so that the cryo-EM image is not blurred by movement.

When they analyzed these images, Noviello, Hibbs, and their colleagues discovered some interesting structural features that helped explain some of the anomalous properties of a7. For example, the negatively charged amino acids in the inner channel of a7 appear to draw positively charged calcium from the outer cells, explaining why a7 is so permeable to calcium. Also, the curved structure of a7 seems to act as a latch to open the gate channel.

The team states that these newly identified structures of a7 can ultimately be used by pharmaceutical companies as a template for developing new drugs that target this and related nicotinic acetylcholine receptors. They will continue to study a7 in a variety of cell types and how it interacts with other molecules and proteins.

“The more we know about this important receptor found in so many different cell types, the better we can understand how it works in physiology and disease,” said Effie Marie Cain Scholar, a medical researcher. Yes Peter O’Donnell Junior Brain Institute..