Our goal is to understand the mechanism by which a large family of transport proteins moves small molecules and ions across biological membranes. In recent years it has become apparent that many families of transport proteins are related at the structural level. The transporter proteins are responsible for moving a wide variety of substrate molecules across cell membranes. They mediate neurotransmitter re-uptake in the brain, sugar and amino acid transport in kidney and intestine, iodide transport in thyroid, and many other important transport processes that are critically important in health and disease. These transporter families are all based on a protein fold containing two structurally similar repeats in opposite orientations relative to the membrane. Recent structural evidence indicates that transport requires a conformational change in which a 4-helix bundle rearranges within the protein structure. However, the ability of these transporters to accumulate substrates within the cell using the coupled movement of ions is a separate issue not addressed by previous studies.
The specific aims of this project are to use biochemical, biophysical and computational approaches to test proposed mechanisms, and to understand how binding of substrate and ions can trigger conformational changes relating to the movement of the bundle and the consequent opening and closing of permeation pathways.
The movement of molecules across cell membranes is critical for many important physiological processes including the function of neurons in the brain, the absorption of nutrients in our diet, and the proper handling of essential minerals such as iodide by the thyroid gland. The molecular structures of a large group of transporter proteins responsible for these and many other processes have recently been found to be closely related. Our goal, to reveal how these related proteins work, will allow a better understanding of the dependent physiological processes and provide a basis for therapy to treat disorders of those processes.
| Zhang, Yuan-Wei; Tavoulari, Sotiria; Sinning, Steffen et al. (2018) Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT. Proc Natl Acad Sci U S A 115:E8854-E8862 |
