Grant: Operating Grant

Each cell in our body is surrounded by a thin membrane made up of specialized lipids and proteins. Some of these membrane proteins allow certain ions like sodium, chloride or bicarbonate to enter or exit the cell. We are studying a bicarbonate/chloride transport protein that is present in our red blood cells and also in acid-secreting cells in the kidney. We would like to find out how this protein works at the molecular level. Studies have indicated that it operates somewhat like a revolving door, where bicarbonate enters as chloride exits. Bicarbonate ions are important for maintaining a proper pH balance within cells and the body. When cells become too acidic through metabolism, bicarbonate enters to neutralize the acid. In the red blood cell, carbon dioxide that builds up in tissues such as muscle enters the cell and is converted to bicarbonate, which then exits the cell via a specific transport protein called AE1, for anion exchanger 1. In the kidney a similar process happens where bicarbonate is moved back into the blood to maintain the pH balance of the body by a kidney form of AE1. Unfortunately, there are inherited mutations in the AE1 gene that result in human diseases that affect bicarbonate transport in the red blood cell and the kidney. We are very interested in determining how these mutations affect the working of the AE1 transport protein. To see how AE1 works, we are trying to determine the structure of this molecular machine using powerful biochemical techniques like X-ray crystallography. One approach we are using is to study similar proteins from bacteria, which are much simpler and easier to study. One goal of our work is to develop drugs that correct the defects in AE1 that may be useful in treating disease.